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Altintas Z, Altintas E. The Impact of Organic Anion-Transporting Polypeptide (OATP) Variants on the Side Effects of Direct-Acting Antivirals in Hepatitis C Patients. Cureus 2025; 17:e82213. [PMID: 40370892 PMCID: PMC12075992 DOI: 10.7759/cureus.82213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2025] [Indexed: 05/16/2025] Open
Abstract
Background Organic anion-transporting polypeptides (OATPs) are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. The aim of our study was to determine whether variations in OATP1B1 and OATP1B3 affect the side effects experienced by hepatitis C patients treated with direct-acting antivirals (DAAs). Methods This study included 199 hepatitis C patients treated with DAAs. Ledipasvir/sofosbuvir or ombitasvir/paritaprevir/ritonavir ± dasabuvir and 162 control individuals without hepatitis C. Treatment-related side effects were recorded. The OATP1B1 gene variations c.388A>G and c.521T>C and the OATP1B3 gene variations c.334T>G and c.699G>A were analyzed via the polymerase chain reaction-restriction fragment length polymorphism method. Allele/genotype combinations of OATP1B1 and OATP1B3 haplotypes were evaluated. Results Side effects were observed in 53 (26.6%) of 199 hepatitis C patients. There were skin mucosal lesions in 19 patients (36%), fatigue in 18 patients (34%), pruritus in 11 patients (20.5%), and other in five patients (9.5%). There was a significant relationship between the c.334T>G variant and side effects (p = 0.030). The frequency distribution of the c.334T>G variant was in Hardy-Weinberg equilibrium. The frequencies of the patient group and the control group were 65.3% and 63%, respectively. We found a significant difference between the patient and control groups in terms of the haplotype ratios of c.388A>G and c.521T>C (p = 0.036). Conclusions We found a significant relationship between the c.334T>G variant in OATP1B3 and DAA-related side effects in hepatitis C patients.
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Affiliation(s)
- Zuhal Altintas
- Medical Genetics, Faculty of Medicine, Mersin University, Mersin, TUR
| | - Engin Altintas
- Gastroenterology and Hepatology, Faculty of Medicine, Mersin University, Mersin, TUR
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Ji Q, Hu Y, Liu M, Liu L, Zheng J, Du Z, Gao L, Xiao P, Ling J, Fan L, Bian X, Lou F, Cao S, Li J, Tian Y, Lu J, Qin J, Hu S. Post-transplant complications revealed by mycophenolate mofetil related transporters and metabolic enzymes gene polymorphisms in pediatric patients with hematological disorders. BMC Cancer 2024; 24:1516. [PMID: 39696070 DOI: 10.1186/s12885-024-13227-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 11/21/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) serves as an important option for patients without an HLA matched donor in treating hematological disorders, while patients may experience various complications after transplantation. Mycophenolate mofetil (MMF), a cornerstone drug for graft-versus-host disease (GvHD) prophylaxis, effectively reduces the incidence of acute GvHD, and the efficacy of MMF varies among individuals associated with MMF-related transporters and metabolic enzymes single nucleotide polymorphisms (SNPs). However, limited studies have systematically reported the correlations between the MMF-related SNPs and post-transplant complications. METHODS Here, we conducted a retrospective study involving 90 pediatric patients with hematological disorders who underwent haplo-HSCT at a single center. All patients were subjected to MMF-related SNP testing, combined with common clinical characteristics, to be correlated with post-transplant complications. RESULTS We observed that all 15 MMF-related SNPs were in Hardy-Weinberg equilibrium. Based on multivariate Cox regression analysis of post-transplant complications, we discovered that SLCO1B1 (521T > C) variant genotype was an independent protective factor for chronic GvHD (HR = 0.25, 95% confidence interval (CI) (0.08-0.84)). For viral infection, CYP2C8 (1291 + 106T > C) variant genotype was an independent risk factor for cytomegalovirus infection (HR = 2.98, 95% CI (1.18-7.53)). As to hemorrhagic cystitis, SLCO1B1 (1865 + 4846T > C) variant genotype was an independent protective factor, while older age was considered as an independent risk factor (HR = 0.41, 95% CI (0.19-0.85); HR = 2.52, 95% CI (1.14-5.54), respectively). No statistical significance was discovered between common clinical characteristics and MMF-related SNPs with other complications, including grade II-IV/III-IV acute GvHD, Epstein-Barr virus infection, peri-engraftment syndrome, and capillary leak syndrome. We also discovered SLCO1B1 (597 C > T) and SLC29A1 (-162 + 228 A > C) variant genotypes are both independent factors for cumulative incidence of relapse after haplo-HSCT (HR = 4.02, 95% CI (1.42-11.44); HR = 0.18, 95% CI (0.07-0.43), respectively). CONCLUSIONS Our findings highlight the significance of MMF-related transporters and metabolic enzymes SNPs in the development of post-transplant complications, contributing to facilitating personalized risk assessment and improving the clinical management in haplo-HSCT patients.
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Affiliation(s)
- Qi Ji
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Yixin Hu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Minyuan Liu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Lixia Liu
- Department of Medical Affairs, Acornmed Biotechnology Co., Ltd, Floor 18, Block 5, Yard 18, Kechuang 13 RD, Beijing, 100176, China
| | - Jiajia Zheng
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Zhizhuo Du
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Li Gao
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Peifang Xiao
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Jing Ling
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Liyan Fan
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Xinni Bian
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Feng Lou
- Department of Medical Affairs, Acornmed Biotechnology Co., Ltd, Floor 18, Block 5, Yard 18, Kechuang 13 RD, Beijing, 100176, China
| | - Shanbo Cao
- Department of Medical Affairs, Acornmed Biotechnology Co., Ltd, Floor 18, Block 5, Yard 18, Kechuang 13 RD, Beijing, 100176, China
| | - Jie Li
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Yuanyuan Tian
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China
| | - Jun Lu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China.
| | - Jiayue Qin
- Department of Medical Affairs, Acornmed Biotechnology Co., Ltd, Floor 18, Block 5, Yard 18, Kechuang 13 RD, Beijing, 100176, China.
| | - Shaoyan Hu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, No. 92, Zhongnan Street, Suzhou, 215002, China.
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Sato T, Kawabata T, Kumondai M, Hayashi N, Komatsu H, Kikuchi Y, Onoguchi G, Sato Y, Nanatani K, Hiratsuka M, Maekawa M, Yamaguchi H, Abe T, Tomita H, Mano N. Effect of Organic Anion Transporting Polypeptide 1B1 on Plasma Concentration Dynamics of Clozapine in Patients with Treatment-Resistant Schizophrenia. Int J Mol Sci 2024; 25:13228. [PMID: 39684938 DOI: 10.3390/ijms252313228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/04/2024] [Accepted: 12/06/2024] [Indexed: 12/18/2024] Open
Abstract
The involvement of drug-metabolizing enzymes and transporters in plasma clozapine (CLZ) dynamics has not been well examined in Japanese patients with treatment-resistant schizophrenia (TRS). Therefore, this clinical study investigated the relationship between single nucleotide polymorphisms (SNPs) of various pharmacokinetic factors (drug-metabolizing enzymes and transporters) and dynamic changes in CLZ. Additionally, we aimed to determine whether CLZ acts as a substrate for pharmacokinetic factors using in vitro assays and molecular docking calculations. We found that 6 out of 10 patients with TRS and with multiple organic anion transporting polypeptide (OATP) variants (OATP1B1: *1b, *15; OATP1B3: 334T>G, 699G>A; and OATP2B1: *3, 935G>A, 601G>A, 76_84del) seemed to be highly exposed to CLZ and/or N-desmethyl CLZ. A CLZ uptake study using OATP-expressing HEK293 cells showed that CLZ was a substrate of OATP1B1 with Km and Vmax values of 38.9 µM and 2752 pmol/mg protein/10 min, respectively. The results of molecular docking calculations supported the differences in CLZ uptake among OATP molecules and the weak inhibitory effect of cyclosporine A, which is a strong inhibitor of OATPs, on CLZ uptake via OATP1B1. This is the first study to show that CLZ is an OATP1B1 substrate and that the presence of SNPs in OATPs potentially alters CLZ pharmacokinetic parameters.
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Affiliation(s)
- Toshihiro Sato
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Takeshi Kawabata
- Graduate School of Information Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Masaki Kumondai
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Nagomi Hayashi
- Faculty of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Hiroshi Komatsu
- Department of Psychiatry, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Yuki Kikuchi
- Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Go Onoguchi
- Department of Psychiatry, Tohoku University Hospital, Sendai 980-8574, Japan
- Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Yu Sato
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Kei Nanatani
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai 980-8573, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan
| | - Masahiro Hiratsuka
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
- Faculty of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai 980-8573, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan
| | - Masamitsu Maekawa
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
- Faculty of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai 980-8573, Japan
| | - Hiroaki Yamaguchi
- Department of Pharmacy, Yamagata University Hospital, Yamagata 990-9585, Japan
- Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan
| | - Takaaki Abe
- Division of Nephrology, Endocrinology, and Vascular Medicine, Graduate School of Medicine, Tohoku University, Sendai 980-8574, Japan
- Division of Medical Science, Graduate School of Biomedical Engineering, Tohoku University, Sendai 980-8579, Japan
- Department of Clinical Biology and Hormonal Regulation, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Hiroaki Tomita
- Department of Psychiatry, Tohoku University Hospital, Sendai 980-8574, Japan
- Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Nariyasu Mano
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
- Faculty of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
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Nađ Škegro S, Penezić L, Šimičević L, Hudolin T, Kaštelan Ž, Božina N, Trkulja V. The reduced function allele SLCO1B1 c.521T>C is of no practical relevance for the renal graft function over the first post-transplant year in patients treated with mycophenolic acid. Pharmacogenet Genomics 2024; 34:226-235. [PMID: 39101384 DOI: 10.1097/fpc.0000000000000539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/06/2024]
Abstract
OBJECTIVE It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. METHODS In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. RESULTS The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17). CONCLUSIONS In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.
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Affiliation(s)
| | - Luka Penezić
- Department of Urology, University Hospital Center Zagreb
| | - Livija Šimičević
- Divison of Pharmacogenomics and Therapy Individualization University Hospital Center Zagreb and Department of Biochemistry and Clinical Chemistry, Zagreb University School of Medicine
| | - Tvrtko Hudolin
- Department of Urology, University Hospital Center Zagreb
- Department of Urology, Zagreb University School of Medicine
| | - Željko Kaštelan
- Department of Urology, University Hospital Center Zagreb
- Department of Urology, Zagreb University School of Medicine
| | - Nada Božina
- Department of Pharmacology, Zagreb University School of Medicine, Zagreb Croatia
| | - Vladimir Trkulja
- Department of Pharmacology, Zagreb University School of Medicine, Zagreb Croatia
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Mao J, Yu F, Qin W, She G, Rong Y, Hu Z, Zhong M. In vitro mechanistic study on mycophenolate mofetil drug interactions: effect of prednisone, cyclosporine, and others. Front Pharmacol 2024; 15:1443794. [PMID: 39253382 PMCID: PMC11381307 DOI: 10.3389/fphar.2024.1443794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/12/2024] [Indexed: 09/11/2024] Open
Abstract
Objective The metabolism- and transporter-based drug-drug interactions (DDIs) between mycophenolate mofetil (MMF) and co-administered medications may be key factors for the high individual variability in MMF exposure. This study systematically assessed the influence of co-medications on the mycophenolic acid (MPA) pharmacokinetic (PK) process in vitro, particularly to provide mechanistic evidence of the metabolic interaction among steroids, cyclosporine (CsA), and MMF. Methods Based on a previous study, we hypothesized that there are three main DDI pathways affecting MMF PK in vivo. A human hepatocyte induction study, transporter substrate/inhibition study using human embryonic kidney 293 cells, and multidrug resistance-associated protein 2 (MRP2) substrate/inhibition study using vesicle membrane were conducted to assess the mechanistic evidence of the metabolic interaction in triple therapies. The potential DDI risks associated with seven medications commonly co-administered with MMF in clinical practice were further evaluated. Results The in vitro results suggested that prednisolone, the active metabolite of prednisone, induces the enzymatic activity of uridine 5'-diphospho-glucuronosyltransferase (UGT), particularly the UGT1A9 and UGT2B7 isoforms, resulting in increased metabolism of MPA to MPA glucuronide (MPAG). This induction potential was not observed in CsA-treated human hepatocytes. CsA inhibits organic anion-transporting polypeptide (OATP) 1B1- and OATP1B3-mediated MPAG. Prednisolone and CsA showed no inhibitory effect on MRP2-mediated MPAG efflux. Salvia miltiorrhiza significantly inhibited organic anion-transporting polypeptide and OAT 3 activities, suggesting that it affects the hepatic uptake and renal excretion of MPAG, causing increased MPAG exposure in vivo. Conclusion These identified factors may contribute to the high inter-individual variability in MMF exposure and facilitate further development of mechanistic MMF PK models and individualized therapies.
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Affiliation(s)
- Junjun Mao
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Feifei Yu
- Vigonvita Life Sciences Co. Ltd., Suzhou, China
| | - Weiwei Qin
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Guixian She
- Research institute for liver diseases (Shanghai) Co. Ltd., Shanghai, China
| | - Yi Rong
- Research institute for liver diseases (Shanghai) Co. Ltd., Shanghai, China
| | - Zhuohan Hu
- Research institute for liver diseases (Shanghai) Co. Ltd., Shanghai, China
| | - Mingkang Zhong
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
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Yow HY, Ikawati M, Siswanto S, Hermawan A, Rahmat AK, Tan JSL, Tee YC, Ng KP, Ikawati Z. Influence of genetic polymorphisms on pharmacokinetics and treatment response of mycophenolic acid: a scoping review. Pharmacogenomics 2024; 25:259-288. [PMID: 38884938 PMCID: PMC11388138 DOI: 10.1080/14622416.2024.2344430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 04/12/2024] [Indexed: 06/18/2024] Open
Abstract
This scoping review explores the impact of genetic polymorphisms on the pharmacokinetics and treatment responses of mycophenolic acid (MPA), an immunosuppressant. The study includes 83 articles from 1226 original studies, focusing on transplantation (n = 80) and autoimmune disorders (n = 3). Genetic variants in uridine 5'-diphospho-glucuronosyltransferase (UGT1A9, UGT1A8 and UGT2B7) and transmembrane transporters (ABCC2, SLCO1B1, SLCO1B3 and ABCB1) significantly affected MPA's pharmacokinetics and susceptibility to its adverse effect. Whereas variants in several genes including UGT1A9, UGT2B7, IMPDH1 and IMPDH2 have been associated with a higher risk of transplant rejection. However, there is a lack of studies on MPA's impact on autoimmune disorders and limited research on the Asian population. The findings underscore the need for further research on MPA's impact across different populations and diseases, particularly among other Asian ethnic groups, to advance personalized medicine in MPA therapy.
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Affiliation(s)
- Hui-Yin Yow
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, 50603, Malaysia
| | - Muthi Ikawati
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, 55281, Indonesia
| | - Soni Siswanto
- Department of Pharmacology & Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, 55281, Indonesia
| | - Adam Hermawan
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, 55281, Indonesia
- Advanced Pharmaceutical Sciences Laboratory, Faculty of Pharmacy, Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, 55281, Indonesia
| | - Alim Khodimul Rahmat
- Department of Pharmacology & Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, 55281, Indonesia
| | - Janet Sui-Ling Tan
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, 50603, Malaysia
| | - Ying-Chew Tee
- Rheumatology Unit, Department of Medicine, University Malaya, Kuala Lumpur, 50603, Malaysia
| | - Kok-Peng Ng
- Nephrology Unit, Department of Medicine, University Malaya, Kuala Lumpur, 50603, Malaysia
| | - Zullies Ikawati
- Department of Pharmacology & Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, 55281, Indonesia
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Nashimoto S, Miyamae M, Higuchi I, Kono M, Tada M, Atsumi T, Sugawara M, Takekuma Y. Decrease in Mycophenolic Acid Plasma Level by Sacubitril/Valsartan in a Lupus Nephritis Patient: A Case Report. Case Rep Nephrol Dial 2024; 14:30-35. [PMID: 38420337 PMCID: PMC10901534 DOI: 10.1159/000536468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 01/20/2024] [Indexed: 03/02/2024] Open
Abstract
Introduction Mycophenolate mofetil (MMF), an inactive prodrug of mycophenolic acid (MPA), is an immunosuppressive drug used widely in the treatment of lupus nephritis. In this case report, the area under the blood concentration time curve (AUC) of MPA was significantly decreased by the concomitant use of sacubitril/valsartan. Case Presentation The patient was a man in his 40s with a diagnosis of lupus nephritis class IVa/c+V. MMF dose was 1.5 g/day at admission, and AUC of MPA on day 14 was 25.1 μg⋅h/mL. Owing to poor blood pressure control, sacubitril/valsartan was initiated at 97/103 mg/day on day 29. On day 37, AUC of MPA was significantly decreased to 8.7 μg⋅h/mL, suggesting drug interaction with the newly initiated sacubitril/valsartan. Sacubitril/valsartan was decreased to 49/51 mg/day, and AUC of MPA on day 67 was 37.6 μg⋅h/mL, achieving the target range. The final MMF dose was set at 1.75 g/day. A possible mechanism of drug interaction between sacubitril/valsartan and MPA involves an organic anion transporting polypeptide (OATP). The inhibition of OATPs by sacubitril may have interrupted the enterohepatic circulation of MPA, resulting in a lower plasma concentration. Conclusion Since lupus nephritis is often associated with hypertension, the drug interaction observed in this report may also occur in other cases. However, it is impossible to conclude that the decrease in plasma MPA levels was due to the concomitant use of sacubitril/valsartan, and more cases and basic findings are needed.
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Affiliation(s)
- Shunsuke Nashimoto
- Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Masashi Miyamae
- Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan
| | - Issei Higuchi
- Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan
| | - Michihito Kono
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Maria Tada
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Mitsuru Sugawara
- Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
- Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan
| | - Yoh Takekuma
- Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan
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Rexiti K, Jiang X, Kong Y, Chen X, Liu H, Peng H, Wei X. Population pharmacokinetics of mycophenolic acid and dose optimisation in adult Chinese kidney transplant recipients. Xenobiotica 2023; 53:603-612. [PMID: 37991412 DOI: 10.1080/00498254.2023.2287168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 11/20/2023] [Indexed: 11/23/2023]
Abstract
1. This study aimed to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA), quantify the effect of clinical factors and pharmacogenomics of MPA, and optimise the dosage for adult kidney transplant recipients.2. One-hundred and four adult renal transplant patients were enrolled. The PPK model was established using the Phoenix® NMLE software and the stepwise methods were filtered for significant covariates. Monte Carlo simulations were performed to optimise the dosage regimen.3. A two-compartment model with first-order absorption and elimination (including lag time) provided a more accurate description of MPA pharmacokinetics. Serum albumin (ALB) significantly affected the central apparent clearance (CL/F), whereas post-transplant time and creatinine clearance were associated with a central apparent volume of distribution (V/F). The estimated population values obtained by the final model were 17.5 L/h and 93.97 L for CL/F and V/F, respectively. Simulation results revealed that larger mycophenolate mofetil doses are required as the ALB concentration decreases. This study established a PPK model of MPA and validated it using various methods. ALB significantly affected CL/F and recommended optimal dose strategies were given based on the final model. These results provide a reference for the personalised therapy of MPA for kidney transplant patients.
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Affiliation(s)
- Kaisaner Rexiti
- School of Pharmacy, Nanchang University, Nanchang, China
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xuehui Jiang
- Department of Pharmacy, Quanzhou First Hospital affiliated to Fujian Medical University, Quanzhou, China
| | - Ying Kong
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xu Chen
- School of Pharmacy, Nanchang University, Nanchang, China
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hong Liu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hongwei Peng
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaohua Wei
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Sun SS, Shao K, Lu JQ, An HM, Shi HQ, Zhou PJ, Chen B. Influence of Calcineurin Inhibitors and Genetic Polymorphism of Transporters on Enterohepatic Circulation and Exposure of Mycophenolic Acid in Chinese Adult Renal Allograft Recipients. J Clin Pharmacol 2023; 63:410-420. [PMID: 36394393 DOI: 10.1002/jcph.2176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 10/14/2022] [Indexed: 11/18/2022]
Abstract
There is significant enterohepatic circulation (EHC) during the disposition of mycophenolic acid (MPA). The aim of this study was to elucidate factors influencing the EHC of MPA in Chinese adult renal allograft recipients. After 2 weeks of therapy with mycophenolate mofetil or enteric-coated mycophenolate sodium, blood samples were collected from 125 patients at 0 to 12 hours post-administration and MPA concentrations were determined. The influence of calcineurin inhibitors (CNIs) and genetic polymorphisms on MPA exposure and EHC was studied. The Shapley additive explanations method was used to estimate the impact of various factors on the area under the plasma drug concentration-time curve (AUC0-12h ) for MPA. An extreme gradient boosting (XGboost) machine learning-based model was established to predict AUC0-12h . Results showed that the dose-normalized AUC6-12h (dn-AUC6-12h ) of MPA was significantly lower in patients co-administered with cyclosporine (CsA) than in patients co-administered with tacrolimus (TAC) (P < .05). For patients co-administered with TAC, patients with ABCC2 C-24T CC or SLCO1B1 T521C TT genotypes had significantly higher values of dn-AUC6-12h (P < .05). Patients with SLCO1B3 334T/699G alleles had significantly lower dn-AUC6-12h values than homozygotes (P < .05). By introducing body weight, age, and EHC-related factors, including co-administered CNIs and genetic polymorphism of drug transporters, as covariates in the XGboost machine learning model, the prediction performance of AUC0-12h for MPA in Chinese adult renal allograft recipients can be improved.
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Affiliation(s)
- Sha-Sha Sun
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kun Shao
- Center for Organ Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia-Qian Lu
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui-Min An
- Center for Organ Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao-Qiang Shi
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pei-Jun Zhou
- Center for Organ Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Chen
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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10
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Rong Y, Kiang T. Clinical Evidence on the Purported Pharmacokinetic Interactions between Corticosteroids and Mycophenolic Acid. Clin Pharmacokinet 2023; 62:157-207. [PMID: 36848031 DOI: 10.1007/s40262-023-01212-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2023] [Indexed: 03/01/2023]
Abstract
Corticosteroids (steroids) are commonly used concurrently with mycophenolic acid (MPA) as the first-line immunosuppression therapy for the prevention of rejection in solid organ transplantations. Steroids are also commonly administered with MPA in various autoimmune disorders such as systemic lupus erythematosus and idiopathic nephrotic syndrome. Despite various review articles having suggested the presence of pharmacokinetic interactions between MPA and steroids, definitive data have not yet been demonstrated. The aim of this Current Opinion is to critically evaluate the available clinical data and propose the optimal study design for characterising the MPA-steroid pharmacokinetic interactions. The PubMed and Embase databases were searched for relevant clinical articles in English as of September 29, 2022, where a total of 8 papers have been identified as supporting and 22 as non-supporting the purported drug interaction. To objectively evaluate the data, novel assessment criteria to effectively diagnose the interaction based on known MPA pharmacology were formulated, including the availability of independent control groups, prednisolone concentrations, MPA metabolite data, unbound MPA concentrations, and the characterisations of entero-hepatic recirculation and MPA renal clearance. Overall, the majority of the identified corticosteroid data were pertaining to prednisone or prednisolone. Our assessment indicated that no conclusive mechanistic data supporting the interaction are available in the current clinical literature, and further studies are required to quantify the effects/mechanisms of steroid-tapering or withdrawal on MPA pharmacokinetics. This current opinion provides justification for further translational investigations, as this particular drug interaction has the potential to exert significant adverse outcomes in patients prescribed MPA.
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Affiliation(s)
- Yan Rong
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Katz Group Centre for Pharmacy and Health Research, Room 3-142D, 11361-87 Avenue, Edmonton, AB, T6G 2E1, Canada
| | - Tony Kiang
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Katz Group Centre for Pharmacy and Health Research, Room 3-142D, 11361-87 Avenue, Edmonton, AB, T6G 2E1, Canada.
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11
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Borić-Bilušić AA, Božina N, Lalić Z, Lovrić M, Nađ-Škegro S, Penezić L, Barišić K, Trkulja V. Loss of Function ABCG2 c.421C>A (rs2231142) Polymorphism Increases Steady-State Exposure to Mycophenolic Acid in Stable Renal Transplant Recipients: An Exploratory Matched Cohort Study. Adv Ther 2023; 40:601-618. [PMID: 36434147 DOI: 10.1007/s12325-022-02378-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/08/2022] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Polymorphism ABCG2 c.421C>A (rs2231142) results in reduced activity of the important drug efflux transporter breast cancer-resistance protein (BCRP/ABCG2). One study has suggested that it may affect enterohepatic recirculation of mycophenolic acid (MPA). We evaluated the effect of rs2231142 on steady-state exposure to MPA in renal transplant recipients. METHODS Consecutive, stable adult (age ≥ 16 years) renal transplant recipients on standard MPA-based immunosuppressant protocols (N = 68; 43 co-treated with cyclosporine, 25 with tacrolimus) underwent routine therapeutic drug monitoring after a week of initial treatment, and were genotyped for ABCG2 c.421C>A and 11 polymorphisms in genes encoding enzymes and transporters implicated in MPA pharmacokinetics. ABCG2 c.421C>A variant versus wild-type (wt) patients were matched with respect to demographic, biopharmaceutic, and genetic variables (full optimal combined with exact matching) and compared for dose-adjusted steady-state MPA pharmacokinetics [frequentist and Bayes (skeptical neutral prior) estimates of geometric means ratios, GMR]. RESULTS Raw data (12 variant versus 56 wt patients) indicated around 40% higher total exposure (frequentist GMR = 1.45, 95% CI 1.10-1.91; Bayes = 1.38, 95% CrI 1.07-1.81) and around 30% lower total body clearance (frequentist GMR = 0.66, 0.58-0.90; Bayes = 0.71, 0.53-0.95) in variant carriers than in wt controls. The estimates were similar in matched data (11 variant versus 43 wt patients): exposure GMR = 1.41 (1.11-1.79) frequentist, 1.39 (1.15-1.81) Bayes, with 90.7% and 85.5% probability of GMR > 1.20, respectively; clearance GMR = 0.73 (0.58-0.93) frequentist, 0.71 (0.54-0.95) Bayes. Sensitivity analysis indicated low susceptibility of the estimates to unmeasured confounding. CONCLUSIONS Loss-off-function polymorphism ABCG2 c.421C>A increases steady-state exposure to MPA in stable renal transplant patients.
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Affiliation(s)
- A Ana Borić-Bilušić
- Agency for Medicinal Products and Medical Devices of Croatia, Zagreb, Croatia
| | - Nada Božina
- Department of Pharmacology, Zagreb University School of Medicine, Šalata 11, 10000, Zagreb, Croatia
| | - Zdenka Lalić
- Department of Laboratory Diagnostics, Analytical Toxicology and Pharmacology Division, University Hospital Center Zagreb, Zagreb, Croatia
| | - Mila Lovrić
- Department of Laboratory Diagnostics, Analytical Toxicology and Pharmacology Division, University Hospital Center Zagreb, Zagreb, Croatia
| | - Sandra Nađ-Škegro
- Department of Urology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Luka Penezić
- Department of Urology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Karmela Barišić
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, Zagreb University, Zagreb, Croatia
| | - Vladimir Trkulja
- Department of Pharmacology, Zagreb University School of Medicine, Šalata 11, 10000, Zagreb, Croatia.
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Islam F, Islam MR, Nafady MH, Faysal M, Khan SL, Zehravi M, Emran TB, Rahman MH. Pharmacogenomics of immunosuppressants. Pharmacogenomics 2023:323-344. [DOI: 10.1016/b978-0-443-15336-5.00003-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023] Open
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13
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Zhong J, Yang K, Zhang M, Wu J, Liu L. SLCO1B3 T334G polymorphisms and mycophenolate mofetil-related adverse reactions in kidney transplant recipients. Pharmacogenomics 2023; 24:83-91. [PMID: 36475448 DOI: 10.2217/pgs-2022-0101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background: The correlation between SLCO1B3 T334G polymorphisms and mycophenolate mofetil (MMF) adverse reactions in kidney recipients is unknown. Methods: A single-center, retrospective study was performed in which 111 patients were divided into four groups according to the type of adverse effect experienced. The clinical data and concentrations of MMF at different months after transplantation were statistically analyzed. Results: The G allele in the gastrointestinal reaction group was significantly higher than that in the no adverse effects group (p < 0.05). Logistic regression model showed that the SLCO1B3 T334G genotype was an independent risk factor for gastrointestinal reactions caused by MMF. Conclusion: Patients with the SLCO1B3 T334G GG genotype were more likely to experience gastrointestinal reactions.
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Affiliation(s)
- Jianxun Zhong
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, 430070, China
| | - Kun Yang
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, 430070, China
| | - Mi Zhang
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, 430070, China
| | - Jianhua Wu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, 430070, China
| | - Liang Liu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, 430070, China
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14
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Ragia G, Atzemian N, Maslarinou A, Manolopoulos VG. SLCO1B1 c.521T>C gene polymorphism decreases hypoglycemia risk in sulfonylurea-treated type 2 diabetic patients. Drug Metab Pers Ther 2022; 37:347-352. [PMID: 36169244 DOI: 10.1515/dmpt-2022-0131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/02/2022] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Pharmacogenomics can explain some of the heterogeneity of sulfonylurea (SU)-related hypoglycemia risk. Recently, a role of OATP1B1, encoded by SLCO1B1 gene, on SU liver transport prior of metabolism has been uncovered. The aim of the present study was to explore the potential association of SLCO1B1 c.521T>C polymorphism, leading to reduced OATP1B1 function, with SU-related hypoglycemia risk. METHODS Study cohort consists of 176 type 2 diabetes patients treated with the SUs glimepiride or gliclazide. 92 patients reported SU-related hypoglycemia, while 84 patients had never experienced a hypoglycemic event. Patients were previously genotyped for CYP2C9 *2 and *3 variant alleles that lead to decreased enzyme activity of the SU metabolizing enzyme CYP2C9 and have been associated with increased SU-related hypoglycemia risk. SLCO1B1 c.521T>C polymorphism was genotyped by use of PCR-RFLP analysis. RESULTS SLCO1B1 c.521TC genotype frequency was significantly lower in hypoglycemic cases than non-hypoglycemic controls (15.2% vs. 32.1%, p=0.008). In an adjusted model, c.521TC genotype significantly reduced the risk of hypoglycemia (OR 0.371; 95% C.I. 0.167-0.822; p=0.015). In CYP2C9 intermediate metabolizers (n=54) c.521TC genotype frequency was significantly decreased in cases compared to controls (3 out of 36 cases, 8.3% vs. 7 out of 18 controls, 38.9%, p=0.012). A similar albeit not significant difference of SLCO1B1 c.521TC genotype was present in CYP2C9 extensive metabolizers (n=120) (18.2% in cases vs. 30.8% in controls, p=0.113). CONCLUSIONS We have found a protective effect of SLCO1B1 c.521C variant on SU-related hypoglycemia risk both independently and in interaction with CYP2C9 phenotypes. Our results suggest a possible linkage of SLCO1B1 c.521T>C polymorphism with variants in other genes impairing OATPs expressed in pancreatic islets that could interfere with SU tissue distribution.
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Affiliation(s)
- Georgia Ragia
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Natalia Atzemian
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Anthi Maslarinou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Vangelis G Manolopoulos
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece.,Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
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15
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Nies AT, Schaeffeler E, Schwab M. Hepatic solute carrier transporters and drug therapy: Regulation of expression and impact of genetic variation. Pharmacol Ther 2022; 238:108268. [DOI: 10.1016/j.pharmthera.2022.108268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/25/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022]
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16
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Abderahmene A, Ellouz A, Amor D, Ajmi M, Khalij Y, Hamdouni H, Sahtout W, Azzabi A, Omezzine A, Achour A, Bouslama A. The pharmacogenetics of mycophenolate mofetil in Tunisian renal transplant patients. Per Med 2022; 19:383-393. [PMID: 35770851 DOI: 10.2217/pme-2021-0092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: The effects of variants in IMPDH, UGT1A9, UGT1A8, UGT2B7 and SLCO1B1 genes on the efficacy and safety of mycophenolate mofetil (MMF) in the Tunisian population were investigated. Materials & methods: A total of 245 kidney transplant patients being treated with MMF were recruited and cotreated with cyclosporine or tacrolimus. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. MMF, cyclosporine and tacrolimus trough levels were measured by immunoassay. The AUC (AUC0-12hMPA) was estimated by a Bayesian method. Results: In the tacrolimus-treated group, anemia and diarrhea were associated with the UGT1A9-98C and UGT1A9-275T alleles, respectively (p < 0.05). In the cyclosporine-treated group, leukopenia was associated with the SLCO1B1-521T allele (p < 0.05). Both groups had an increased risk of rejection (p < 0.05) associated with the variant alleles of IMPDH2-3757T>C, UGT1A9-2152C>T and UGT1A9-275C>A and the common allele of SLCO1B1-388A>G. However, no significant association was found between the studied genotypes and AUC0-12hMPA or cotreatment levels. Conclusion: The results constitute preliminary evidence for the inclusion of the pharmacogenetics of MMF in kidney pretransplantation evaluations.
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Affiliation(s)
- Amani Abderahmene
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Amel Ellouz
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Dorra Amor
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Marwa Ajmi
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Higher Institute of Biotechnology of Monastir, Street Taher Hadded, 5000, Monastir, Tunisia
| | - Yassine Khalij
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Haithem Hamdouni
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Wissal Sahtout
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Awatef Azzabi
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Asma Omezzine
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Abdellatif Achour
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Ali Bouslama
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
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17
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Association Study of SLCO1B3 and ABCC3 Genetic Variants in Gallstone Disease. Genes (Basel) 2022; 13:genes13030512. [PMID: 35328066 PMCID: PMC8951115 DOI: 10.3390/genes13030512] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 12/10/2022] Open
Abstract
There is growing evidence that gallstone formation may be genetically determined. Recent studies have shown that polymorphism of genes encoding proteins involved in bile acid transport may be associated with the risk of gallstone disease. The aim of this study was to investigate the association between SLCO1B3 (rs4149117:G>T, rs7311358:A>G) and ABCC3 (rs4793665:T>C, rs11568591:G>A) genetic variants and susceptibility to cholesterol gallstone disease, as well as gallstone composition. The study included 317 patients suffering from cholelithiasis who underwent cholecystostomy and 249 controls with no evidence of stones, confirmed by ultrasound examination. There were no statistically significant differences in the distribution of studied gene polymorphisms between patients with gallstone disease and healthy controls. No significant associations were observed between studied genotypes and the content of analyzed gallstone components: total cholesterol, bilirubin, CaCO3, nor the total bile acids. There was also no association between bile acid content in gallstones and the polymorphisms studied. The results of this study suggest that polymorphisms of SLCO1B3 and ABCC3 genes are not a valuable marker of gallstone disease susceptibility and do not influence gallstone composition.
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18
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Significant Correlations between p-Cresol Sulfate and Mycophenolic Acid Plasma Concentrations in Adult Kidney Transplant Recipients. Clin Drug Investig 2022; 42:207-219. [PMID: 35182318 DOI: 10.1007/s40261-022-01121-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND AND OBJECTIVES Mycophenolic acid (MPA) is a commonly prescribed life-long immunosuppressant for kidney transplant recipients. The frequently observed large variations in MPA plasma exposure may lead to severe adverse outcomes; therefore, characterizations of contributing factors can potentially improve the precision dosing of MPA. Our group recently reported the potent inhibitory effects of p-cresol (a protein-bound uremic toxin that can be accumulated in kidney transplant patients) on the hepatic metabolism of MPA in human in vitro models. Based on these data, the hypothesis for this clinical investigation was that a direct correlation between p-cresol and MPA plasma exposure should be evident in adult kidney transplant recipients. METHODS Using a prospective and observational approach, adult kidney transplant recipients within the first year after transplant on oral mycophenolate mofetil (with tacrolimus ± prednisone) were screened for recruitment. The exclusion criteria were cold ischemia time > 30 h, malignancy, pregnancy, severe renal dysfunction (i.e., estimated glomerular filtration rate, eGFR, < 10 mL/min/1.73 m2), active graft rejection, or MPA intolerance. Patients' demographic and biochemistry data were collected. Total and free plasma concentrations of MPA, MPA glucuronide (MPAG), and total p-cresol sulfate (the predominant, quantifiable form of p-cresol in the plasma) were quantified using validated assays. Correlational and categorical analyses were performed using GraphPad Prism. RESULTS Forty patients (11 females) were included: donor type (living/deceased: 20/20), induction regimen (basiliximab/thymoglobulin/basiliximab followed by thymoglobulin: 35/3/2), post-transplant time (74 ± 60 days, mean ± standard deviation), age (53.7 ± 12.4 years), bodyweight (79.8 ± 18.5 kg), eGFR (51.9 ± 18.0 mL/min/1.73 m2), serum albumin (3.6 ± 0.5 g/dL), prednisone dose (18.5 ± 13.2 mg, n = 33), and tacrolimus trough concentration (9.4 ± 2.4 µg/L). Based on Spearman analysis, significant control correlations supporting the validity of our dataset were observed between total MPA trough concentration (C0) and total MPAG C0 (correlation coefficient [R] = 0.39), ratio of total MPAG C0-to-total MPA C0 and post-transplant time (R = - 0.56), total MPAG C0 and eGFR (R = - 0.35), and p-cresol sulfate concentration and eGFR (R = - 0.70). Our primary analysis indicated the novel observation that total MPA C0 (R = 0.39), daily dose-normalized total MPA C0 (R = 0.32), and bodyweight-normalized total MPA C0 (R = 0.32) were significantly correlated with plasma p-cresol sulfate concentrations. Consistently, patients categorized with elevated p-cresol sulfate concentrations (i.e., ≥ median of 3.2 µg/mL) also exhibited increased total MPA C0 (by 57 % vs those below median), daily dose-normalized total MPA C0 (by 89 %), and bodyweight-normalized total MPA C0 (by 62 %). Our secondary analyses with MPA metabolites, unbound concentrations, free fractions, and MPA metabolite ratios supported additional potential interacting mechanisms. CONCLUSION We have identified a novel, positive association between p-cresol sulfate exposure and total MPA C0 in adult kidney transplant recipients, which is supported by published mechanistic in vitro data. Our findings confirm a potential role of p-cresol as a significant clinical variable affecting the pharmacokinetics of MPA. These data also provide the justifications for conducting subsequent full-scale pharmacokinetic-pharmacodynamic studies to further characterize the cause-effect relationships of this interaction, which could also rule out potential confounding variables not adequately controlled in this correlational study.
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Wankaew N, Chariyavilaskul P, Chamnanphon M, Assawapitaksakul A, Chetruengchai W, Pongpanich M, Shotelersuk V. Genotypic and phenotypic landscapes of 51 pharmacogenes derived from whole-genome sequencing in a Thai population. PLoS One 2022; 17:e0263621. [PMID: 35176049 PMCID: PMC8853512 DOI: 10.1371/journal.pone.0263621] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 01/22/2022] [Indexed: 12/30/2022] Open
Abstract
Differences in drug responses in individuals are partly due to genetic variations in pharmacogenes, which differ among populations. Here, genome sequencing of 171 unrelated Thai individuals from all regions of Thailand was used to call star alleles of 51 pharmacogenes by Stargazer, determine allele and genotype frequencies, predict phenotype and compare high-impact variant frequencies between Thai and other populations. Three control genes, EGFR, VDR, and RYR1, were used, giving consistent results. Every individual had at least three genes with variant or altered phenotype. Forty of the 51 pharmacogenes had at least one individual with variant or altered phenotype. Moreover, thirteen genes had at least 25% of individuals with variant or altered phenotype including SLCO1B3 (97.08%), CYP3A5 (88.3%), CYP2C19 (60.82%), CYP2A6 (60.2%), SULT1A1 (56.14%), G6PD (54.39%), CYP4B1 (50.00%), CYP2D6 (48.65%), CYP2F1 (46.41%), NAT2 (40.35%), SLCO2B1 (28.95%), UGT1A1 (28.07%), and SLCO1B1 (26.79%). Allele frequencies of high impact variants from our samples were most similar to East Asian. Remarkably, we identified twenty predicted high impact variants which have not previously been reported. Our results provide information that contributes to the implementation of pharmacogenetic testing in Thailand and other Southeast Asian countries, bringing a step closer to personalized medicine.
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Affiliation(s)
- Natnicha Wankaew
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Pajaree Chariyavilaskul
- Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Monpat Chamnanphon
- Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Pathology, Faculty of Medicine, Srinakharinwirot University, Nakornnayok, Thailand
| | - Adjima Assawapitaksakul
- Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand
| | - Wanna Chetruengchai
- Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand
| | - Monnat Pongpanich
- Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Age-related Inflammation and Degeneration Research Unit, Chulalongkorn University, Bangkok, Thailand
- * E-mail:
| | - Vorasuk Shotelersuk
- Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand
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Järvinen E, Deng F, Kiander W, Sinokki A, Kidron H, Sjöstedt N. The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates. Front Pharmacol 2022; 12:802539. [PMID: 35095509 PMCID: PMC8793843 DOI: 10.3389/fphar.2021.802539] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/06/2021] [Indexed: 12/11/2022] Open
Abstract
Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.
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Affiliation(s)
- Erkka Järvinen
- Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark
| | - Feng Deng
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Wilma Kiander
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Alli Sinokki
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Heidi Kidron
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Noora Sjöstedt
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
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21
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Rong Y, Patel V, Kiang TKL. Recent lessons learned from population pharmacokinetic studies of mycophenolic acid: physiological, genomic, and drug interactions leading to the prediction of drug effects. Expert Opin Drug Metab Toxicol 2022; 17:1369-1406. [PMID: 35000505 DOI: 10.1080/17425255.2021.2027906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Mycophenolic acid (MPA) is a widely used immunosuppressant in transplantation and autoimmune disease. Highly variable pharmacokinetics have been observed with MPA, but the exact mechanisms remain largely unknown. AREAS COVERED The current review provided a critical, comprehensive update of recently published population pharmacokinetic/dynamic models of MPA (n=16 papers identified from PubMed and Embase, inclusive from January 2017 to August 2021), with specific emphases on the intrinsic and extrinsic factors influencing the pharmacology of MPA. The significance of the identified covariates, potential mechanisms, and comparisons to historical literature have been provided. EXPERT OPINION While select covariates affecting the population pharmacokinetics of MPA are consistently observed and mechanistically supported, some variables have not been regularly reported and/or lacked mechanistic explanation. Very few pharmacodynamic models were available, pointing to the need to extrapolate pharmacokinetic findings. Ideal models of MPA should consist of: i) utilizing optimal sampling points to allow the characterizations of absorption, re-absorption, and elimination phases; ii) characterizing unbound/total MPA, MPA metabolites, plasma/urinary concentrations, and genetic polymorphisms to facilitate mechanistic interpretations; and iii) incorporating actual outcomes and pharmacodynamic data to establish clinical relevance. We anticipate the field will continue to expand in the next 5 to 10 years.
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Affiliation(s)
- Yan Rong
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Vrunda Patel
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Tony K L Kiang
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
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22
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Brazeau D, Meaney CJ, Consiglio JD, Wilding GE, Cooper LM, Venuto RC, Tornatore KM. Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients. J Clin Pharmacol 2021; 61:1592-1605. [PMID: 34169529 PMCID: PMC9358627 DOI: 10.1002/jcph.1932] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 06/21/2021] [Indexed: 11/07/2022]
Abstract
Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance-associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes -24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross-sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0-12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0-12h . The wild-type haplotype ABCC2 CGC had greater mycophenolic acid AUC0-12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0-12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine-mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.
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Affiliation(s)
- Daniel Brazeau
- Department of Pharmacy Practice Administration and Research, School of Pharmacy, Marshall University; Huntington, WV
| | - Calvin J. Meaney
- Transplantation Immunosuppressive Pharmacology Research Program, Translational Pharmacology Research Core, Buffalo NY
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo NY
| | - Joseph D. Consiglio
- Department of Biostatistics, School of Public Health and Health Professions, University at Buffalo, Buffalo NY
| | - Gregory E. Wilding
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo NY
| | - Louise M. Cooper
- Transplantation Immunosuppressive Pharmacology Research Program, Translational Pharmacology Research Core, Buffalo NY
| | - Rocco C. Venuto
- Department of Medicine; Nephrology Division, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo NY
- Dr. Venuto in deceased
| | - Kathleen M. Tornatore
- Transplantation Immunosuppressive Pharmacology Research Program, Translational Pharmacology Research Core, Buffalo NY
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo NY
- Department of Medicine; Nephrology Division, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo NY
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23
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Schumacher L, Fang F, Kidwell KM, Shakeel F, Hertz DL, Park JM, Pasternak AL. SLCO1B3 polymorphisms and clinical outcomes in kidney transplant recipients receiving mycophenolate. Pharmacogenomics 2021; 22:1111-1120. [PMID: 34612072 DOI: 10.2217/pgs-2021-0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Determine the influence of SLCO1B3 polymorphisms on outcomes in kidney transplant recipients. Materials & methods: We retrospectively evaluated 181 adult kidney transplant recipients receiving mycophenolate. Outcomes included treated biopsy-proven acute rejection (tBPAR), de novo donor-specific antibody (dnDSA) formation, graft survival, patient survival and mycophenolate-related adverse effects among SLCO1B3 genotypes. Results: The presence of SLCO1B3 variants was not associated with increased risk of tBPAR (HR: 1.45, 95% CI: 0.76-2.74), dnDSA (HR: 0.46, 95% CI: 0.16-1.36) or composite of tBPAR or dnDSA (HR: 1.14, 95% CI: 0.64-2.03). Graft and patient survival were reduced among variant carriers; however, inconsistent findings with the primary analysis suggest these associations were not due to genotype. Adverse effects were similar between groups. Conclusion: Presence of SLCO1B3 polymorphisms were not predictive of rejection or dnDSA in kidney transplant recipients.
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Affiliation(s)
| | - Fang Fang
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Kelley M Kidwell
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Faisal Shakeel
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA
| | - Daniel L Hertz
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA
| | - Jeong M Park
- Department of Pharmacy, Michigan Medicine, Ann Arbor, MI 48109, USA.,Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA
| | - Amy L Pasternak
- Department of Pharmacy, Michigan Medicine, Ann Arbor, MI 48109, USA.,Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA
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24
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Jiang Z, Hu N. Effect of UGT polymorphisms on pharmacokinetics and adverse reactions of mycophenolic acid in kidney transplant patients. Pharmacogenomics 2021; 22:1019-1040. [PMID: 34581204 DOI: 10.2217/pgs-2021-0087] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Mycophenolic acid (MPA) is a common immunosuppressive drug for kidney transplantation patients, and is characterized by a narrow therapeutic index and significant individual variability. UGTs are the main enzymes responsible for the metabolism of MPA. Although, many studies have focused on the relationship between UGT polymorphisms and pharmacokinetics and adverse reactions of MPA, the conclusion are controversial. We reviewed the relevant literature and summarized the significant influences of UGT polymorphisms, such as UGT1A8 (rs1042597, rs17863762), UGT1A9 (rs72551330, rs6714486, rs17868320, rs2741045, rs2741045) and UGT2B7 (rs7438135, rs7439366, rs7662029), on the pharmacokinetics of MPA and its metabolites and adverse reactions. The review provides a reference for guiding the individualized administration of MPA and reducing adverse reactions to MPA.
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Affiliation(s)
- Zhenwei Jiang
- Department of Pharmacy, The Third Affiliated Hospital of Soochow University, Jiangsu Province, Changzhou, 213000, China
| | - Nan Hu
- Department of Pharmacy, The Third Affiliated Hospital of Soochow University, Jiangsu Province, Changzhou, 213000, China
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25
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Yang CL, Sheng CC, Liao GY, Su Y, Feng LJ, Xia Q, Jiao Z, Xu DJ. Genetic polymorphisms in metabolic enzymes and transporters have no impact on mycophenolic acid pharmacokinetics in adult kidney transplant patients co-treated with tacrolimus: A population analysis. J Clin Pharm Ther 2021; 46:1564-1575. [PMID: 34312870 DOI: 10.1111/jcpt.13488] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/05/2021] [Accepted: 07/01/2021] [Indexed: 12/17/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Mycophenolate mofetil, an ester prodrug of mycophenolic acid (MPA), is widely used to prevent graft rejection after kidney transplantation. The pharmacokinetic (PK) of MPA has been extensively studied, which revealed a high degree of variability. An integrated population PK (PopPK) model of MPA and its main metabolite mycophenolic acid glucuronide (MPAG) was developed using the adult patients who underwent kidney transplant and were administered oral mycophenolate mofetil combined with tacrolimus. METHODS In total, 917 MPA and 740 MPAG concentrations in191 adult patients were analysed via nonlinear mixed-effects modelling. The concentration-time data were adequately described using a chain compartment model, including central and peripheral compartments for MPA and a central compartment for MPAG. Stepwise forward inclusion and backward elimination procedures were used to investigate the effects of genetic polymorphisms, including in UGT1A8, UGT1A9, UGT2B7, ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, and HNF1α. RESULTS AND DISCUSSION These genetic polymorphisms in metabolic enzymes and transporters have no obvious impact on the PK of MPA in adult patients who underwent kidney transplant and were co-treated with tacrolimus. The post-transplant time, serum albumin, and creatinine clearance were identified as significant covariates affecting the PK of MPA and MPAG, which should be considered in the clinical use of mycophenolate mofetil. WHAT IS NEW AND CONCLUSION We established a PopPK model of MPA and MPAG in Chinese adult patients who underwent kidney transplant and were co-treated with tacrolimus. Genetic polymorphisms in metabolic enzymes and transporters showed no obvious impact on MMF PK. A model-informed dosing strategy was proposed by the established model, and MMF dose adjustment should be based on ALB levels and the post-transplantation time.
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Affiliation(s)
- Chun-Lan Yang
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chang-Cheng Sheng
- Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang, China
| | - Gui-Yi Liao
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yong Su
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li-Juan Feng
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Quan Xia
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zheng Jiao
- Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Du-Juan Xu
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China
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26
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Na Takuathung M, Sakuludomkan W, Koonrungsesomboon N. The Impact of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid: Systematic Review and Meta-analysis. Clin Pharmacokinet 2021; 60:1291-1302. [PMID: 34105062 DOI: 10.1007/s40262-021-01037-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND Mycophenolic acid (MPA) is among the most commonly prescribed medications for immunosuppression following organ transplantation. Highly variable MPA exposure and drug response are observed among individuals receiving the same dosage of the drug. Identification of candidate genes whose polymorphisms could be used to predict MPA exposure and clinical outcome is of clinical value. OBJECTIVES This study aimed to determine the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of MPA in humans by means of a systematic review and meta-analysis. METHODS A systematic search was conducted on PubMed, EMBASE, Web of Sciences, Scopus, and the Cochrane Library databases. A meta-analysis was conducted to determine any associations between genetic polymorphisms and pharmacokinetic or pharmacodynamic parameters of MPA. Pooled-effect estimates were calculated by means of the random-effects model. RESULTS A total of 37 studies involving 3844 individuals were included in the meta-analysis. Heterozygous carriers of the UGT1A9 -275T>A polymorphism were observed to have a significantly lower MPA exposure than wild-type individuals. Four single nucleotide polymorphisms (SNPs), namely UGT1A9 -2152C>T, UGT1A8 518C>G, UGT2B7 211G>T, and SLCO1B1 521T>C, were also significantly associated with altered MPA pharmacokinetics. However, none of the investigated SNPs, including SNPs in the IMPDH gene, were found to be associated with the clinical efficacy of MPA. The only SNP that was associated with adverse outcomes was SLCO1B3 344T>G. CONCLUSIONS The present systematic review and meta-analysis identified six SNPs that were significantly associated with pharmacokinetic variability or adverse effects of MPA. Our findings represent the basis for future research and clinical implications with regard to the role of pharmacogenetics in MPA pharmacokinetics and drug response.
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Affiliation(s)
- Mingkwan Na Takuathung
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Road, Sriphoom, Muang, Chiang Mai, 50200, Thailand
| | - Wannachai Sakuludomkan
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Road, Sriphoom, Muang, Chiang Mai, 50200, Thailand
| | - Nut Koonrungsesomboon
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Road, Sriphoom, Muang, Chiang Mai, 50200, Thailand.
- Musculoskeletal Science and Translational Research (MSTR) Center, , Chiang Mai University, Muang, Chiang Mai, Thailand.
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27
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Bergan S, Brunet M, Hesselink DA, Johnson-Davis KL, Kunicki PK, Lemaitre F, Marquet P, Molinaro M, Noceti O, Pattanaik S, Pawinski T, Seger C, Shipkova M, Swen JJ, van Gelder T, Venkataramanan R, Wieland E, Woillard JB, Zwart TC, Barten MJ, Budde K, Dieterlen MT, Elens L, Haufroid V, Masuda S, Millan O, Mizuno T, Moes DJAR, Oellerich M, Picard N, Salzmann L, Tönshoff B, van Schaik RHN, Vethe NT, Vinks AA, Wallemacq P, Åsberg A, Langman LJ. Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit 2021; 43:150-200. [PMID: 33711005 DOI: 10.1097/ftd.0000000000000871] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/29/2021] [Indexed: 12/13/2022]
Abstract
ABSTRACT When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.
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Affiliation(s)
- Stein Bergan
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Kamisha L Johnson-Davis
- Department of Pathology, University of Utah Health Sciences Center and ARUP Laboratories, Salt Lake City, Utah
| | - Paweł K Kunicki
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warszawa, Poland
| | - Florian Lemaitre
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, Rennes, France
| | - Pierre Marquet
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | - Mariadelfina Molinaro
- Clinical and Experimental Pharmacokinetics Lab, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Ofelia Noceti
- National Center for Liver Tansplantation and Liver Diseases, Army Forces Hospital, Montevideo, Uruguay
| | | | - Tomasz Pawinski
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warszawa, Poland
| | | | - Maria Shipkova
- Synlab TDM Competence Center, Synlab MVZ Leinfelden-Echterdingen GmbH, Leinfelden-Echterdingen, Germany
| | - Jesse J Swen
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Teun van Gelder
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy and Department of Pathology, Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Eberhard Wieland
- Synlab TDM Competence Center, Synlab MVZ Leinfelden-Echterdingen GmbH, Leinfelden-Echterdingen, Germany
| | - Jean-Baptiste Woillard
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | - Tom C Zwart
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Markus J Barten
- Department of Cardiac- and Vascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Maja-Theresa Dieterlen
- Department of Cardiac Surgery, Heart Center, HELIOS Clinic, University Hospital Leipzig, Leipzig, Germany
| | - Laure Elens
- Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics (PMGK) Research Group, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Vincent Haufroid
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique, UCLouvain and Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Satohiro Masuda
- Department of Pharmacy, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Olga Millan
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Tomoyuki Mizuno
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Dirk J A R Moes
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Michael Oellerich
- Department of Clinical Pharmacology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany
| | - Nicolas Picard
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | | | - Burkhard Tönshoff
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nils Tore Vethe
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Alexander A Vinks
- Department of Pharmacy, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Pierre Wallemacq
- Clinical Chemistry Department, Cliniques Universitaires St Luc, Université Catholique de Louvain, LTAP, Brussels, Belgium
| | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet and Department of Pharmacy, University of Oslo, Oslo, Norway; and
| | - Loralie J Langman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study. Drugs R D 2021; 20:331-342. [PMID: 33025511 PMCID: PMC7691413 DOI: 10.1007/s40268-020-00319-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background and Objective Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone. Methods Total and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data. Results Mycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and the ABCB1 3435 C>T (rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells. Conclusion This population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation. Electronic supplementary material The online version of this article (10.1007/s40268-020-00319-y) contains supplementary material, which is available to authorized users.
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29
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Rong Y, Jun H, Kiang TKL. Population pharmacokinetics of mycophenolic acid in paediatric patients. Br J Clin Pharmacol 2021; 87:1730-1757. [PMID: 33118201 DOI: 10.1111/bcp.14590] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 09/07/2020] [Accepted: 09/22/2020] [Indexed: 12/14/2022] Open
Abstract
Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or pharmacodynamic modelling has been frequently used to characterize the fixed, random and covariate effects of MPA in adult patients. However, MPA population pharmacokinetic data in the paediatric population have not been systematically summarized. The objective of this narrative review was to provide an up-to-date critique of currently available paediatric MPA population pharmacokinetic models, with emphases on modelling techniques, pharmacological findings and clinical relevance. PubMed and EMBASE were searched from inception of database to May 2020, where a total of 11 studies have been identified representing kidney transplant (n = 4), liver transplant (n = 1), haematopoietic stem cell transplant (n = 1), idiopathic nephrotic syndrome (n = 2), systemic lupus erythematosus (n = 2), and a combined population consisted of kidney, liver and haematopoietic stem cell transplant patients (n = 1). Critical analyses were provided in the context of MPA absorption, distribution, metabolism, excretion and bioavailability in this paediatric database. Comparisons to adult patients were also provided. With respect to clinical utility, Bayesian estimation models (n = 6) with acceptable accuracy and precision for MPA exposure determination have also been identified and systematically evaluated. Overall, our analyses have identified unique features of MPA clinical pharmacology in the paediatric population, while recognizing several gaps that still warrant further investigations. This review can be used by pharmacologists and clinicians for improving MPA pharmacokinetic-pharmacodynamic modelling and patient care.
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Affiliation(s)
- Yan Rong
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Heajin Jun
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.,College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Tony K L Kiang
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
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30
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Genvigir FDV, Campos-Salazar AB, Felipe CR, Tedesco-Silva H, Medina-Pestana JO, Doi SDQ, Cerda A, Hirata MH, Herrero MJ, Aliño SF, Hirata RDC. CYP3A5*3 and CYP2C8*3 variants influence exposure and clinical outcomes of tacrolimus-based therapy. Pharmacogenomics 2020; 21:7-21. [PMID: 31849280 DOI: 10.2217/pgs-2019-0120] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Aim: The influence of variants in pharmacokinetics-related genes on long-term exposure to tacrolimus (TAC)-based therapy and clinical outcomes was investigated. Patients & methods: Brazilian kidney recipients were treated with TAC combined with everolimus (n = 178) or mycophenolate sodium (n = 97). The variants in CYP2C8, CYP2J2, CYP3A4, CYP3A5, POR, ABCB1, ABCC2, ABCG2, SLCO1B1 and SLCO2B1 were analyzed. Main results: CYP3A5*3/*3 genotype influenced increase in TAC concentration from week 1 to month 6 post-transplantation (p < 0.05). The living donor and CYP2C8*3 variant were associated with reduced risk for delayed graft function (OR = 0.07; 95% CI = 0.03-0.18 and OR = 0.45; 95% CI = 0.20-0.99, respectively, p < 0.05). Conclusion: The CYP3A5*3 variant is associated with increased early exposure to TAC. Living donor and CYP2C8*3 variant seem to be protective factors for delayed graft function in kidney recipients.
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Affiliation(s)
- Fabiana Dalla Vecchia Genvigir
- Department of Clinical & Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Antony Brayan Campos-Salazar
- Department of Clinical & Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.,Bioinformatics & Pharmacogenetics Laboratory, METOSMOD Research Group, School of Pharmacy & Biochemistry, Universidad Nacional Mayor de San Marcos, Lima, Peru
| | - Claudia Rosso Felipe
- Nephrology Division, Hospital do Rim, Federal University of Sao Paulo, Sao Paulo, Brazil
| | - Helio Tedesco-Silva
- Nephrology Division, Hospital do Rim, Federal University of Sao Paulo, Sao Paulo, Brazil
| | | | - Sonia de Quateli Doi
- Nephrology Research Laboratory, School of Medicine, Uniformed Services University, Bethesda, MD, USA
| | - Alvaro Cerda
- Department of Basic Sciences, Center of Excellence in Translational Medicine, BIOREN, Universidad de La Frontera, Temuco, Chile
| | - Mario Hiroyuki Hirata
- Department of Clinical & Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - María José Herrero
- Department of Pharmacology, University of Valencia. Pharmacogenetics, Instituto Investigación Sanitaria y Hospital La Fe, Valencia, Spain
| | - Salvador Francisco Aliño
- Department of Pharmacology, University of Valencia. Pharmacogenetics, Instituto Investigación Sanitaria y Hospital La Fe, Valencia, Spain
| | - Rosario Dominguez Crespo Hirata
- Department of Clinical & Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
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Berthier J, Benmameri M, Sauvage FL, Fabre G, Chantemargue B, Arnion H, Marquet P, Trouillas P, Picard N, Saint-Marcoux F. MRP4 is responsible for the efflux transport of mycophenolic acid β-d glucuronide (MPAG) from hepatocytes to blood. Xenobiotica 2020; 51:105-114. [PMID: 32820679 DOI: 10.1080/00498254.2020.1813352] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Mycophenolic acid (MPA) has become a cornerstone of immunosuppressive therapy, in particular for transplant patients. In the gastrointestinal tract, the liver and the kidney, MPA is mainly metabolized into phenyl-β-d glucuronide (MPAG). Knowledge about the interactions between MPA/MPAG and membrane transporters is still fragmented. The aim of the present study was to explore these interactions with the basolateral hepatic MRP4 transporter. The inhibition of the MRP4-driven transport by various drugs which can be concomitantly prescribed was also evaluated. In vitro experiments using vesicles overexpressing MRP4 showed an ATP-dependent transport of MPAG driven by MRP4 (Michaelis-Menten constant of 233.9 ± 32.8 µM). MPA was not effluxed by MRP4. MRP4-mediated transport of MPAG was inhibited (from -43% to -84%) by ibuprofen, cefazolin, cefotaxime and micafungin. An in silico approach based on molecular docking and molecular dynamics simulations rationalized the mode of binding of MPAG to MRP4. The presence of the glucuronide moiety in MPAG was highlighted as key, being prone to make electrostatic and H-bond interactions with specific residues of the MRP4 protein chamber. This explains why MPAG is a substrate of MRP4 whereas MPA is not.
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Affiliation(s)
- Joseph Berthier
- INSERM, UMR 1248, Univ. Limoges, Limoges, France.,CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France
| | | | | | - Gabin Fabre
- INSERM, UMR 1248, Univ. Limoges, Limoges, France
| | | | | | - Pierre Marquet
- INSERM, UMR 1248, Univ. Limoges, Limoges, France.,CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France
| | - Patrick Trouillas
- INSERM, UMR 1248, Univ. Limoges, Limoges, France.,RCPTM, Univ. Palacký of Olomouc, Olomouc, Czech Republic
| | - Nicolas Picard
- INSERM, UMR 1248, Univ. Limoges, Limoges, France.,CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France
| | - Franck Saint-Marcoux
- INSERM, UMR 1248, Univ. Limoges, Limoges, France.,CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France
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32
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Han F, Oliveira H, Brás NF, Fernandes I, Cruz L, De Freitas V, Mateus N. In vitro gastrointestinal absorption of red wine anthocyanins – Impact of structural complexity and phase II metabolization. Food Chem 2020; 317:126398. [DOI: 10.1016/j.foodchem.2020.126398] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 01/16/2020] [Accepted: 02/10/2020] [Indexed: 12/11/2022]
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Salvadori M, Tsalouchos A. Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy. World J Transplant 2020; 10:90-103. [PMID: 32864355 PMCID: PMC7428791 DOI: 10.5500/wjt.v10.i5.90] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/26/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose. Indeed, pharmacogenetics may exert its action on immunosuppressant drugs at three levels. Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation. Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants. Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways. Of course, not all genes have been discovered and studied, but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined. Other genes on the basis of relevant studies have been proposed as good candidates for future studies. Unfortunately, to date, clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney, heart and lung transplantation is recommended. The conclusions of the studies on the recommended candidate genes, together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
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34
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Marin JJG, Serrano MA, Monte MJ, Sanchez-Martin A, Temprano AG, Briz O, Romero MR. Role of Genetic Variations in the Hepatic Handling of Drugs. Int J Mol Sci 2020; 21:E2884. [PMID: 32326111 PMCID: PMC7215464 DOI: 10.3390/ijms21082884] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/09/2020] [Accepted: 04/17/2020] [Indexed: 12/18/2022] Open
Abstract
The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.
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Affiliation(s)
- Jose J. G. Marin
- HEVEFARM Group, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.A.S.); (M.J.M.); (A.S.-M.); (A.G.T.); (O.B.); (M.R.R.)
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35
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Tague LK, Byers DE, Hachem R, Kreisel D, Krupnick AS, Kulkarni HS, Chen C, Huang HJ, Gelman A. Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid. THE PHARMACOGENOMICS JOURNAL 2020; 20:69-79. [PMID: 30992538 PMCID: PMC6800829 DOI: 10.1038/s41397-019-0086-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 01/20/2019] [Accepted: 03/27/2019] [Indexed: 12/18/2022]
Abstract
Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan-Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37-44.04), p = 0.021; rs4149117 HR 7.28 (1.27-41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06-3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13-4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.
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Affiliation(s)
- Laneshia K Tague
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO, USA
| | - Derek E Byers
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO, USA
| | - Ramsey Hachem
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO, USA
| | - Daniel Kreisel
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University in Saint Louis, Saint Louis, MO, USA
| | - Alexander S Krupnick
- Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Hrishikesh S Kulkarni
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO, USA
| | - Catherine Chen
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Howard J Huang
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Andrew Gelman
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University in Saint Louis, Saint Louis, MO, USA.
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36
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Benjanuwattra J, Pruksakorn D, Koonrungsesomboon N. Mycophenolic Acid and Its Pharmacokinetic Drug‐Drug Interactions in Humans: Review of the Evidence and Clinical Implications. J Clin Pharmacol 2019; 60:295-311. [DOI: 10.1002/jcph.1565] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 11/08/2019] [Indexed: 12/14/2022]
Affiliation(s)
| | - Dumnoensun Pruksakorn
- Musculoskeletal Science and Translational Research Center Chiang Mai University Chiang Mai Thailand
- Department of Orthopedics, Faculty of Medicine Chiang Mai University Chiang Mai Thailand
| | - Nut Koonrungsesomboon
- Department of Pharmacology, Faculty of Medicine Chiang Mai University Chiang Mai Thailand
- Musculoskeletal Science and Translational Research Center Chiang Mai University Chiang Mai Thailand
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37
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Model based development of tacrolimus dosing algorithm considering CYP3A5 genotypes and mycophenolate mofetil drug interaction in stable kidney transplant recipients. Sci Rep 2019; 9:11740. [PMID: 31409869 PMCID: PMC6692323 DOI: 10.1038/s41598-019-47876-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 07/19/2019] [Indexed: 01/10/2023] Open
Abstract
This study quantifies the interaction between tacrolimus (TAC) and mycophenolate mofetil (MMF) in kidney transplant recipients. Concentrations of TAC, mycophenolic acid (MPA), and metabolites were analyzed and relevant genotypes were determined from 32 patients. A population model was developed to estimate the effect of interaction. Concentrations of TAC were simulated in clinical scenarios and dose-adjusted trough concentrations per dose (C/D) were compared. Effect of interaction was described as the inverse exponential relationship. Major determinants of trough levels of TAC were CYP3A5 genotype and interaction with MPA. The absolute difference in C/D of TAC according to co-administered MMF was higher in CYP3A5 non-expressers (0.55 ng/mL) than in CYP3A5 expressers (0.35 ng/mL). The effect of MMF in determining the TAC exposure is more pronounced in CYP3A5 non-expressers. Based on population pharmacokinetic model, we suggest the TAC dosing algorithm considering the effects of CYP3A5 and MMF drug interaction in stable kidney transplant recipients.
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38
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Malagnino V, Duthaler U, Seibert I, Krähenbühl S, Meyer Zu Schwabedissen HE. OATP1B3-1B7 (LST-3TM12) Is a Drug Transporter That Affects Endoplasmic Reticulum Access and the Metabolism of Ezetimibe. Mol Pharmacol 2019; 96:128-137. [PMID: 31127008 DOI: 10.1124/mol.118.114934] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 05/15/2019] [Indexed: 02/14/2025] Open
Abstract
Drug transporters play a crucial role in pharmacokinetics. One subfamily of transporters with proven clinical relevance are the OATP1B transporters. Recently we identified a new member of the OATP1B family named OATP1B3-1B7 (LST-3TM12). This functional transporter is encoded by SLCO1B3 and SLCO1B7 OATP1B3-1B7 is expressed in hepatocytes and is located in the membrane of the smooth endoplasmic reticulum (SER). One aim of this study was to test whether OATP1B3-1B7 interacts with commercial drugs. First, we screened a selection of OATP1B substrates for inhibition of OATP1B3-1B7-mediated transport of dehydroepiandrosterone sulfate and identified several inhibitors. One such inhibitor was ezetimibe, which not only inhibited OATP1B3-1B7 but is also a substrate, as its cellular content was significantly increased in cells heterologously expressing the transporter. In humans, ezetimibe is extensively metabolized by hepatic and intestinal uridine-5'-diphospho-glucuronosyltransferases (UGTs), the catalytic site of which is located within the SER lumen. After verification of OATP1B3-1B7 expression in the small intestine, we determined in microsomes whether SER access can be modulated by inhibitors of OATP1B3-1B7. We were able to show that these compounds significantly reduced accumulation in small intestinal and hepatic microsomes, which influenced the rate of ezetimibe β-D-glucuronide formation as determined in microsomes treated with bromsulphthalein. Notably, this molecule not only inhibits the herein reported transporter but also other transport systems. In conclusion, we report that multiple drugs interact with OATP1B3-1B7; for ezetimibe, we were able to show that SER access and metabolism is significantly reduced by bromsulphthalein, which is an inhibitor of OATP1B3-1B7. SIGNIFICANCE STATEMENT: OATP1B3-1B3 (LST-3TM12) is a transporter that has yet to be fully characterized. We provide valuable insight into the interaction potential of this transporter with several marketed drugs. Ezetimibe, which interacted with OATP1B3-1B7, is highly metabolized by uridine-5'-diphospho-glucuronosyltransferases (UGTs), whose catalytic site is located within the smooth endoplasmic reticulum (SER) lumen. Through microsomal assays with ezetimibe and the transport inhibitor bromsulphthalein we investigated the interdependence of SER access and the glucuronidation rate of ezetimibe. These findings led us to the hypothesis that access or exit of drugs to the SER is orchestrated by SER transporters such as OATP1B3-1B7.
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Affiliation(s)
- Vanessa Malagnino
- Biopharmacy, Department of Pharmaceutical Sciences, University of Basel (V.M., I.S., H.E.M.S.) and Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel and University Hospital Basel (U.D., S.K.), Basel, Switzerland
| | - Urs Duthaler
- Biopharmacy, Department of Pharmaceutical Sciences, University of Basel (V.M., I.S., H.E.M.S.) and Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel and University Hospital Basel (U.D., S.K.), Basel, Switzerland
| | - Isabell Seibert
- Biopharmacy, Department of Pharmaceutical Sciences, University of Basel (V.M., I.S., H.E.M.S.) and Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel and University Hospital Basel (U.D., S.K.), Basel, Switzerland
| | - Stephan Krähenbühl
- Biopharmacy, Department of Pharmaceutical Sciences, University of Basel (V.M., I.S., H.E.M.S.) and Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel and University Hospital Basel (U.D., S.K.), Basel, Switzerland
| | - Henriette E Meyer Zu Schwabedissen
- Biopharmacy, Department of Pharmaceutical Sciences, University of Basel (V.M., I.S., H.E.M.S.) and Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel and University Hospital Basel (U.D., S.K.), Basel, Switzerland
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Nie Y, Yang J, Liu S, Sun R, Chen H, Long N, Jiang R, Gui C. Genetic polymorphisms of human hepatic OATPs: functional consequences and effect on drug pharmacokinetics. Xenobiotica 2019; 50:297-317. [DOI: 10.1080/00498254.2019.1629043] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Yingmin Nie
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Jingjie Yang
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Shuai Liu
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Ruiqi Sun
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Huihui Chen
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Nan Long
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Rui Jiang
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Chunshan Gui
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
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40
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Fu Q, Chen M, Anderson JT, Sun X, Hu S, Sparreboom A, Baker SD. Interaction Between Sex and Organic Anion-Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib-N-Oxide and Regorafenib-Glucuronide in Mice. Clin Transl Sci 2019; 12:400-407. [PMID: 30955241 PMCID: PMC6662550 DOI: 10.1111/cts.12630] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 02/02/2019] [Indexed: 12/27/2022] Open
Abstract
Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5′‐diphosphate glucuronosyltransferase (Ugt)1a9‐mediated glucuronidation to form regorafenib‐N‐β‐glucuronide (M7; RG), but the contribution of hepatic uptake transporters, such as organic anion‐transporting polypeptide (Oatp)1b2, to the pharmacokinetics of regorafenib remains poorly understood. Using NONMEM‐based, population‐based, parent‐metabolite modeling, we found that Oatp1b2 and sex strongly impact the systemic exposure to RG in mice receiving oral regorafenib. Metabolic studies revealed that the liver microsomal expression of cytochrome P450 (Cyp)3a11 is twofold lower in female mice, whereas Ugt1a9 levels and function are not sex dependent. This finding is consistent with the metabolism of regorafenib occurring via two competing pathways, and the lack of Oatp1b2 results in decreased clearance of RG. The described model provides mechanistic insights into the in vivo disposition of regorafenib.
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Affiliation(s)
- Qiang Fu
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Mingqing Chen
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Jason T Anderson
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Xinxin Sun
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Sharyn D Baker
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
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Yang F, Liu L, Chen L, Liu M, Liu F, Xiong Y, Hu X, Xia C. OATP1B3 (699G>A) and CYP2C9*2, *3 significantly influenced the transport and metabolism of glibenclamide and glipizide. Sci Rep 2018; 8:18063. [PMID: 30584236 PMCID: PMC6305483 DOI: 10.1038/s41598-018-36212-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 11/16/2018] [Indexed: 11/24/2022] Open
Abstract
Glibenclamide and glipizide show large substantial inter-individual variation in clinical efficacy, which may be resulted from the genetic differences of metabolic enzymes and transporters in individuals. This study purposed to investigate the effect of OATP1B3 and CYP2C9 genetic polymorphisms on the transport and metabolism of glibenclamide and glipizide in human. An LC-MS method was used to determine the uptake of glibenclamide and glipizide in OATP1B3, OATP1B3 (344T > G) and OATP1B3 (699G > A)-HEK293T cells and their metabolism in CYP2C9*1, *2 and *3 recombinase system. Glibenclamide can be taken in OATP1B3 (wild-type), OATP1B3 (344T > G) and OATP1B3 (699G > A)-HEK293T cells with the Vmax values of 44.91 ± 7.97, 46.08 ± 8.69, and 37.31 ± 5.04 pmol/min/mg, while glipizide was taken in with Vmax of 16.50 ± 3.64, 16.87 ± 4.23, and 13.42 ± 2.79 pmol/min/mg, respectively. The internal clearance of glibenclamide and glipizide in OATP1B3 (699G > A) was less than that in wild-type. Glibenclamide can be metabolized in CYP2C9*1, *2 and *3 recombinase system with the Vmax values of 1.58 ± 0.71, 0.69 ± 0.25, and 0.41 ± 0.13 nmol/min/mg protein, while glipizide was metabolized with Vmax of 8.82 ± 2.78, 5.99 ± 1.95, and 2.87 ± 1.03 nmol/min/mg protein, respectively. The internal clearance of glibenclamide and glipizide in CYP2C9*2 and *3 was markedly reduced compared to that in CYP2C9*1. These results collectively demonstrate that OATP1B3 (699G > A) and CYP2C9*2 and *3 have a significant influence on the transport and metabolism of glibenclamide and glipizide.
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Affiliation(s)
- Fayou Yang
- Clinical Pharmacology Institute, Nanchang University, Nanchang, 330006, P.R. China
| | - Linlin Liu
- Nanchang Hongdu Hospital of TCM, Nanchang, 330038, P.R. China
| | - Lin Chen
- Nanchang Hongdu Hospital of TCM, Nanchang, 330038, P.R. China
| | - Mingyi Liu
- Clinical Pharmacology Institute, Nanchang University, Nanchang, 330006, P.R. China
| | - Fanglan Liu
- Clinical Pharmacology Institute, Nanchang University, Nanchang, 330006, P.R. China
| | - Yuqing Xiong
- Clinical Pharmacology Institute, Nanchang University, Nanchang, 330006, P.R. China
| | - Xiao Hu
- Clinical Pharmacology Institute, Nanchang University, Nanchang, 330006, P.R. China
| | - Chunhua Xia
- Clinical Pharmacology Institute, Nanchang University, Nanchang, 330006, P.R. China.
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Li LQ, Chen DN, Li CJ, Li QP, Chen Y, Fang P, Zheng P, Lu HJ, Ye DM, Wan HY, Li J, Li L. Impact of UGT2B7 and ABCC2 genetic polymorphisms on mycophenolic acid metabolism in Chinese renal transplant recipients. Pharmacogenomics 2018; 19:1323-1334. [PMID: 30345879 DOI: 10.2217/pgs-2018-0114] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
AIM To evaluate genetic variants affecting mycophenolic acid (MPA) metabolism in Chinese renal transplant recipients. METHODS Total 11 SNPs of UGT1A9, UGT1A8, UGT2B7, ABCC2, ABCG2 and SLCO1B3 were genotyped in 408 Chinese renal transplant recipients. Associations between SNPs and MPA concentration/dose ratio (C0/D) were analyzed using different genetic models. Multivariate linear regression was used to analyze associations between log (C0/D) and clinical factors. Results: After adjustment by clinical factors, UGT2B7 rs7662029 was associated with log (C0/D) using a dominant (p = 0.041) and an additive (p = 0.038) model, ABCC2 rs717620 was associated with log (C0/D) using a recessive model (p = 0.019). Using additive model, SNP-SNP interactions were identified (p = 0.002) between ABCC2 rs717620 and UGT1A9 rs2741049, with interactions (p = 0.002) between ABCC2 rs717620 and UGT1A8 rs1042597. Age, albumin and serum creatinine were associated with log (C0/D). CONCLUSION rs7662029 and rs717620 may affect MPA pharmacokinetics. SNP-SNP interactions and clinical factors may have significant effects on MPA metabolism.
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Affiliation(s)
- Li-Qing Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Di-Na Chen
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Chuan-Jiang Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Qing-Ping Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Yan Chen
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Ping Fang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Ping Zheng
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Hui-Jie Lu
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - De-Mei Ye
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Hao-Yang Wan
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Jie Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, PR China
| | - Liang Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, PR China.,Key Laboratory of single cell technology and application in Guangzhou, Guangdong, PR China
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Zhang B, Lauschke VM. Genetic variability and population diversity of the human SLCO (OATP) transporter family. Pharmacol Res 2018; 139:550-559. [PMID: 30359687 DOI: 10.1016/j.phrs.2018.10.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 09/14/2018] [Accepted: 10/17/2018] [Indexed: 01/12/2023]
Abstract
Organic anion transporting polypeptides (OATP) encoded by the SLCO gene family constitute clinically important transporters involved in the disposition of endogenous compounds and many commonly prescribed drugs, including statins, methotrexate and antihypertensive medications. Common genetic polymorphisms in SLCO genes are known to affect OATP function and modulate efficacy and safety of OATP substrates. However, current frequency data of these variants and haplotypes is generally based on few rather heterogenous populations of relatively small sample size. Furthermore, the genetic variability beyond these selected pharmacogenetic biomarkers has not been systematically analyzed. Here, we provide a global consolidated map of SLCO variability by leveraging fully compatible Next Generation Sequencing data from 138,632 unrelated individuals across seven major human populations. Overall, we find 9811 exonic single nucleotide variants and 155 copy number variations of which 99.3% were rare with frequencies <1%. Using orthogonal computational functionality predictors optimized for pharmacogenetic assessments, we find that four out of five individuals carry at least one deleterious variant in an SLCO transporter gene and rare variants contribute 23% to the genetically encoded functional variability. Moreover, 74.9% of all variants were found to be population-specific with important consequences for population-specific genotyping strategies and precision public health approaches. Combined, our analyses provide the most comprehensive data set of SLCO variability published to date and incentivize the integration of comprehensive NGS-based genotyping into personalized predictions of OATP substrate disposition.
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Affiliation(s)
- Boyao Zhang
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Volker M Lauschke
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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Yap DYH, Tam CH, Yung S, Wong S, Tang CSO, Mok TMY, Yuen CKY, Ma MKM, Lau CS, Chan TM. Pharmacokinetics and pharmacogenomics of mycophenolic acid and its clinical correlations in maintenance immunosuppression for lupus nephritis. Nephrol Dial Transplant 2018; 35:810-818. [DOI: 10.1093/ndt/gfy284] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 07/18/2018] [Indexed: 01/02/2023] Open
Abstract
Abstract
Background
There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term maintenance.
Methods
We measured blood MPA levels at 1, 2, 4, 8, 10 and 12-h post-dose (i.e. C1, C2, C4, C8, C10 and C12) in 88 stable LN patients receiving maintenance prednisolone and mycophenolate mofetil, repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate–binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs17222723), organic anion-transporting polypeptides (OATPs; rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330) was also investigated.
Results
C1, C2 and C12 were 8.3 ± 6.6 , 7.2 ± 5.2 and 2.0 ± 1.4 mg/L and all correlated with the 12-h area under the curve (AUC0–12; r = 0.51, 0.85 and 0.73; P = 0.02, <0.001 and <0.001, respectively). C12 inversely correlated with hemoglobin, immunoglobulins and leukocyte levels (P < 0.05 for all). Five renal flares, 11 episodes of infection and 10 episodes of anemia (hemoglobin <10 g/dL) occurred over 96 weeks, with a corresponding C12 of 1.3 ± 0.5, 4.3 ± 2.6 and 2.9 ± 1.5 mg/L, respectively (versus 2.4 ± 1.2, 1.8 ± 1.2 and 1.7 ± 1.1 mg/L in patients without these complications; P = 0.041, <0.001 and 0.004). SNP rs2273697 A/G in the ABCC2 gene was associated with lower MPA exposure compared with G/G (1075.9 ± 239.9 versus 1891.5 ± 918.9 mgh/L per g/kg; P = 0.003). SNPs of OATP and UGT were unrelated to MPA level.
Conclusion
MPA C12 correlates with the AUC0–12 and is related to renal flare, infection and anemia. SNP rs2273697 A/G is associated with lower MPA exposure.
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Affiliation(s)
- Desmond Y H Yap
- Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong
| | - Chun Hay Tam
- Nephrology Division, Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong
| | - Susan Yung
- Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong
| | - Sunny Wong
- Nephrology Division, Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong
| | - Colin S O Tang
- Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong
| | - Temy M Y Mok
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Hong Kong, Hong Kong
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong
| | - Catherine K Y Yuen
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Hong Kong, Hong Kong
| | - Maggie K M Ma
- Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong
| | - Chak Sing Lau
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Hong Kong, Hong Kong
| | - Tak Mao Chan
- Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong
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Jabir RS, Ho GF, Annuar MABA, Stanslas J. Association of Allelic Interaction of Single Nucleotide Polymorphisms of Influx and Efflux Transporters Genes With Nonhematologic Adverse Events of Docetaxel in Breast Cancer Patients. Clin Breast Cancer 2018; 18:e1173-e1179. [PMID: 29885788 DOI: 10.1016/j.clbc.2018.04.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 02/19/2018] [Accepted: 04/23/2018] [Indexed: 12/11/2022]
Abstract
PURPOSE Nonhematologic adverse events (AEs) of docetaxel constitute an extra burden in the treatment of cancer patients and necessitate either a dose reduction or an outright switch of docetaxel for other regimens. These AEs are frequently associated with genetic polymorphisms of genes encoding for proteins involved docetaxel disposition. Therefore, we investigated that association in Malaysian breast cancer patients. MATERIALS AND METHODS A total of 110 Malaysian breast cancer patients were enrolled in the present study, and their blood samples were investigated for different single nucleotide polymorphisms using polymerase chain reaction restriction fragment length polymorphism. AEs were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS Fatigue, nausea, oral mucositis, and vomiting were the most common nonhematologic AEs. Rash was associated with heterozygous and mutant genotypes of ABCB1 3435C>T (P < .05). Moreover, patients carrying the GG genotype of ABCB1 2677G>A/T reported more fatigue than those carrying the heterozygous genotype GA (P < .05). The presence of ABCB1 3435-T, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-G alleles was significantly associated with nausea and oral mucositis. The coexistence of ABCB1 3435-C, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-A was significantly associated with vomiting (P < .05). CONCLUSION The prevalence of nonhematologic AEs in breast cancer patients treated with docetaxel has been relatively high. The variant allele of ABCB1 3435C>T polymorphism could be a potential predictive biomarker of docetaxel-induced rash, and homozygous wild-type ABCB1 2677G>A/T might predict for a greater risk of fatigue. In addition, the concurrent presence of specific alleles could be predictive of vomiting, nausea, and oral mucositis.
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Affiliation(s)
- Rafid Salim Jabir
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - Gwo Fuang Ho
- Clinical Oncology Unit, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Muhammad Azrif Bin Ahmad Annuar
- Department of Radiotherapy and Oncology, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur, Malaysia
| | - Johnson Stanslas
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia.
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Matsunaga N, Fukuchi Y, Imawaka H, Tamai I. Sandwich-Cultured Hepatocytes for Mechanistic Understanding of Hepatic Disposition of Parent Drugs and Metabolites by Transporter-Enzyme Interplay. Drug Metab Dispos 2018; 46:680-691. [PMID: 29352067 DOI: 10.1124/dmd.117.079236] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 01/17/2018] [Indexed: 12/13/2022] Open
Abstract
Functional interplay between transporters and drug-metabolizing enzymes is currently one of the hottest topics in the field of drug metabolism and pharmacokinetics. Uptake transporter-enzyme interplay is important to determine intrinsic hepatic clearance based on the extended clearance concept. Enzyme and efflux transporter interplay, which includes both sinusoidal (basolateral) and canalicular efflux transporters, determines the fate of metabolites formed in the liver. As sandwich-cultured hepatocytes (SCHs) maintain metabolic activities and form a canalicular network, the whole interplay between uptake and efflux transporters and drug-metabolizing enzymes can be investigated simultaneously. In this article, we review the utility and applicability of SCHs for mechanistic understanding of hepatic disposition of both parent drugs and metabolites. In addition, the utility of SCHs for mimicking species-specific disposition of parent drugs and metabolites in vivo is described. We also review application of SCHs for clinically relevant prediction of drug-drug interactions caused by drugs and metabolites. The usefulness of mathematical modeling of hepatic disposition of parent drugs and metabolites in SCHs is described to allow a quantitative understanding of an event in vitro and to develop a more advanced model to predict in vivo disposition.
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Affiliation(s)
- Norikazu Matsunaga
- Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan (N.M. Y.F., H.I.); Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (I.T.)
| | - Yukina Fukuchi
- Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan (N.M. Y.F., H.I.); Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (I.T.)
| | - Haruo Imawaka
- Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan (N.M. Y.F., H.I.); Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (I.T.)
| | - Ikumi Tamai
- Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan (N.M. Y.F., H.I.); Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (I.T.)
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Cascorbi I. The Pharmacogenetics of Immune-Modulating Therapy. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2018; 83:275-296. [PMID: 29801578 DOI: 10.1016/bs.apha.2018.02.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Immunosuppressive drugs are a prerequisite in organ transplantation to prevent rejection and are also widely used in inflammatory diseases such as inflammatory bowel disease (IBD) or also in some hematologic malignancies-depending on the mode of action. For thiopurine analogs the polymorphic thiopurine S-methyltransferase (TPMT) was early detected to be associated with thiopurine-induced leukopenia; recent studies identified also NUDT15 to be related to this severe side effect. For drugs like methotrexate and mycophenolate mofetil a number of ADME genes like UDP-glucuronosyltransferases (UGTs) and ABC efflux transporters were investigated, however, with partly contradicting results. For calcineurin inhibitors like cyclosporine and in particular tacrolimus however, cytochrome P450 3A4 and 3A5 variants were found to significantly affect the pharmacokinetics. Genetic variants in genes encoding relevant pharmacodynamic proteins, however, lacked compelling evidence to affect the clinical outcome. This chapter reviews the current evidence on the association of pharmacogenetic traits to dose finding and clinical outcome of small-molecule immunosuppressants. Moreover this chapter critically summarizes suitability to apply pharmacogenetics in clinical practice in order to optimize immunosuppressant therapy.
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Affiliation(s)
- Ingolf Cascorbi
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany.
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48
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Alam K, Crowe A, Wang X, Zhang P, Ding K, Li L, Yue W. Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions. Int J Mol Sci 2018. [PMID: 29538325 PMCID: PMC5877716 DOI: 10.3390/ijms19030855] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important hepatic transporters that mediate the uptake of many clinically important drugs, including statins from the blood into the liver. Reduced transport function of OATP1B1 and OATP1B3 can lead to clinically relevant drug-drug interactions (DDIs). Considering the importance of OATP1B1 and OATP1B3 in hepatic drug disposition, substantial efforts have been given on evaluating OATP1B1/1B3-mediated DDIs in order to avoid unwanted adverse effects of drugs that are OATP substrates due to their altered pharmacokinetics. Growing evidences suggest that the transport function of OATP1B1 and OATP1B3 can be regulated at various levels such as genetic variation, transcriptional and post-translational regulation. The present review summarizes the up to date information on the regulation of OATP1B1 and OATP1B3 transport function at different levels with a focus on potential impact on OATP-mediated DDIs.
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Affiliation(s)
- Khondoker Alam
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
| | - Alexandra Crowe
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
| | - Xueying Wang
- Center for Computational Biology and Bioinformatics, Indiana Institute of Personalized Medicine, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Pengyue Zhang
- Center for Computational Biology and Bioinformatics, Indiana Institute of Personalized Medicine, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Kai Ding
- Department of Biostatistics and Epidemiology, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.
| | - Lang Li
- Center for Computational Biology and Bioinformatics, Indiana Institute of Personalized Medicine, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
- Department of Biomedical Informatics, Ohio State University, Columbus, OH 43210, USA.
| | - Wei Yue
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
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Nakano K, Iwami D, Yamada T, Morita K, Yasuda K, Shibuya H, Kahata K, Shinohara N, Shimizu C. Development of a Formula to Correct Particle-Enhanced Turbidimetric Inhibition Immunoassay Values so That it More Precisely Reflects High-Performance Liquid Chromatography Values for Mycophenolic Acid. Transplant Direct 2018; 4:e337. [PMID: 29399626 PMCID: PMC5777668 DOI: 10.1097/txd.0000000000000754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 10/21/2017] [Indexed: 11/25/2022] Open
Abstract
Background Mycophenolic acid (MPA) concentration measured by homogeneous particle-enhanced turbidimetric inhibition immunoassay (PETINA) may be overestimated due to its cross-reactivity with pharmacologically inactive MPA glucuronide (MPAG), as well as other minor metabolites, accumulated with renal function impairment or co-administered cyclosporine A. In contrast, high-performance liquid chromatography (HPLC) is precise because it can exclude the cross-reactivity. In this study, we assumed HPLC values for MPA (HPLC-MPA) as a reference and aimed to develop a formula correcting PETINA values for MPA (PETINA-MPA) to more precisely reflect HPLC-MPA. Methods MPA trough concentrations were measured both by HPLC-UV and PETINA in 39 samples issued from 39 solid-organ transplant recipients. MPAG concentrations were also measured using HPLC UV assay. We determined the impacts of renal function and coadministered calcineurin inhibitor on concentrations of MPA and MPAG measured by HPLC. Then, we evaluated the difference between PETINA-MPA and HPLC-MPA. Finally, we develop a formula to reflect HPLC-MPA by using multilinear regression analysis. Results MPAG concentration was negatively correlated with estimated glomerular filtration rate (eGFR) (R2 = 0.376, P < 0.001), although MPA was not correlated with eGFR. There were no significant differences in MPA or MPAG concentrations per dose between the patients who were co-administered tacrolimus versus cyclosporine A. Finally, we developed the formulas to reflect HPLC-MPA:Formula 1: Estimated MPA concentration = 0.048 + 0.798 × PETINA-MPAFormula 2: Estimated MPA concentration = - 0.059 + 0.800 × PETINA-MPA + 0.002 × eGFRHowever, there was no significant improvement in the coefficient of determination with addition of eGFR in the formula, suggesting that HPLC-MPA can be well predicted by only 1 variable, PETINA-MPA. Conclusions This study developed a formula so that PETINA-MPA can be corrected to more precisely reflect HPLC-MPA.
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Affiliation(s)
- Keiichi Nakano
- Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan
| | - Daiki Iwami
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | - Takehiro Yamada
- Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan
| | - Ken Morita
- Department of Urology, Kushiro City General Hospital, Kushiro, Japan
| | - Keiko Yasuda
- Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan
| | - Hitoshi Shibuya
- Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan
| | - Kaoru Kahata
- Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan
| | - Nobuo Shinohara
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | - Chikara Shimizu
- Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan
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Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers. Sci Rep 2018; 8:1687. [PMID: 29374217 PMCID: PMC5786104 DOI: 10.1038/s41598-018-20071-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 01/12/2018] [Indexed: 01/05/2023] Open
Abstract
The objective of the study was to investigate the pharmacokinetic drug-drug interactions between tacrolimus (TAC) and mycophenolate mofetil (MMF) in healthy Korean male volunteers. Seventeen volunteers participated in a three-period, single-dose, and fixed sequence study. They sequentially received MMF, TAC, and the combination. Concentrations of TAC, mycophenolic acid (MPA), and its metabolites MPA 7-O-glucuronide and MPA acyl glucuronide were measured. The variants of CYP3A4, CYP3A5, SLCO1B1, SLCO1B3, ABCC2, UGT1A9, and UGT2B7 were genotyped. Drug interaction was evaluated with a non-compartmental analysis and population pharmacokinetic modelling to quantify the interaction effect. A total of 1,082 concentrations of those analytes were analysed. AUC0-inf of TAC increased by 22.1% (322.4 ± 174.1 to 393.6 ± 121.7 ng·h/mL; P < 0.05) when co-administered with MMF, whereas the pharmacokinetic parameters of MPA and its metabolites were not changed by TAC. Apparent clearance (CL/F) of TAC was 17.8 L/h [relative standard error (RSE) 11%] or 13.8 L/h (RSE 11%) without or with MMF, respectively. Interaction was explained by the exponential model. The CYP3A5 genotype was the only significant covariate. The population estimate of CL/F of TAC was 1.48-fold (RSE 16%) in CYP3A5 expressers when compared to nonexpressers. CL/F of TAC was decreased when co-administered with MMF in these subjects.
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