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Stone SJ. Mechanisms of intestinal triacylglycerol synthesis. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159151. [PMID: 35296424 DOI: 10.1016/j.bbalip.2022.159151] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/13/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023]
Abstract
Triacylglycerols are a major source of stored energy that are obtained either from the diet or can be synthesized to some extent by most tissues. Alterations in pathways of triacylglycerol metabolism can result in their excessive accumulation leading to obesity, insulin resistance, cardiovascular disease and nonalcoholic fatty liver disease. Most tissues in mammals synthesize triacylglycerols via the glycerol 3-phosphate pathway. However, in the small intestine the monoacylglycerol acyltransferase pathway is the predominant pathway for triacylglycerol biosynthesis where it participates in the absorption of dietary triacylglycerol. In this review, the enzymes that are part of both the glycerol 3-phosphate and monoacylglycerol acyltransferase pathways and their contributions to intestinal triacylglycerol metabolism are reviewed. The potential of some of the enzymes involved in triacylglycerol synthesis in the small intestine as possible therapeutic targets for treating metabolic disorders associated with elevated triacylglycerol is briefly discussed.
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Affiliation(s)
- Scot J Stone
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
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2
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The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains. Pharmaceuticals (Basel) 2021; 15:ph15010049. [PMID: 35056106 PMCID: PMC8780580 DOI: 10.3390/ph15010049] [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: 11/30/2021] [Revised: 12/21/2021] [Accepted: 12/27/2021] [Indexed: 12/02/2022] Open
Abstract
Pregnanolone glutamate (PA-G) is a neuroactive steroid that has been previously demonstrated to be a potent neuroprotective compound in several biological models in vivo. Our in vitro experiments identified PA-G as an inhibitor of N-methyl-D-aspartate receptors and a potentiator of γ-aminobutyric acid receptors (GABAARs). In this study, we addressed the hypothesis that combined GABAAR potentiation and NMDAR antagonism could afford a potent anticonvulsant effect. Our results demonstrated the strong age-related anticonvulsive effect of PA-G in a model of pentylenetetrazol-induced seizures. PA-G significantly decreased seizure severity in 12-day-old animals, but only after the highest dose in 25-day-old animals. Interestingly, the anticonvulsant effect of PA-G differed both qualitatively and quantitatively from that of zuranolone, an investigational neurosteroid acting as a potent positive allosteric modulator of GABAARs. Next, we identified 17-hydroxy-pregnanolone (17-OH-PA) as a major metabolite of PA-G in 12-day-old animals. Finally, the administration of PA-G demonstrated direct modulation of unexpected neurosteroid levels, namely pregnenolone and dehydroepiandrosterone sulfate. These results suggest that compound PA-G might be a pro-drug of 17-OH-PA, a neurosteroid with a promising neuroprotective effect with an unknown mechanism of action that may represent an attractive target for studying perinatal neural diseases.
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Coombes Z, Plant K, Freire C, Basit AW, Butler P, Conlan RS, Gonzalez D. Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue. Pharmaceutics 2021; 13:pharmaceutics13101707. [PMID: 34684000 PMCID: PMC8537901 DOI: 10.3390/pharmaceutics13101707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/05/2021] [Accepted: 10/12/2021] [Indexed: 11/16/2022] Open
Abstract
Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. This novel information can inform decisions on the development of targeted formulations and help predict dosage regimens.
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Affiliation(s)
- Zoe Coombes
- Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School, Singleton Park, Swansea SA2 8PP, UK; (Z.C.); (R.S.C.)
| | - Katie Plant
- Cyprotex, No.24 Mereside, Alderley Park, Nether Alderley, Cheshire SK10 4TG, UK; (K.P.); (P.B.)
| | | | - Abdul W. Basit
- Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK;
| | - Philip Butler
- Cyprotex, No.24 Mereside, Alderley Park, Nether Alderley, Cheshire SK10 4TG, UK; (K.P.); (P.B.)
| | - R. Steven Conlan
- Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School, Singleton Park, Swansea SA2 8PP, UK; (Z.C.); (R.S.C.)
| | - Deyarina Gonzalez
- Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School, Singleton Park, Swansea SA2 8PP, UK; (Z.C.); (R.S.C.)
- Correspondence: ; Tel.: +44-1792-295384
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Baur AC, Brandsch C, Steinmetz B, Schutkowski A, Wensch-Dorendorf M, Stangl GI. Differential effects of vitamin D 3 vs vitamin D 2 on cellular uptake, tissue distribution and activation of vitamin D in mice and cells. J Steroid Biochem Mol Biol 2020; 204:105768. [PMID: 33035648 DOI: 10.1016/j.jsbmb.2020.105768] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 07/12/2020] [Accepted: 09/29/2020] [Indexed: 10/23/2022]
Abstract
To combat vitamin D deficiency, vitamin D3 and vitamin D2 are commonly used as a supplement or to fortify food sources. Human data show that the response of 25-hydroxyvitamin D (25(OH)D) to supplementation with vitamin D3 is higher than to vitamin D2. To elucidate the metabolic route of both vitamers, we conducted a study with vitamin D-depleted mice, which were allotted into three groups (n = 12) and received equal doses of either deuterated vitamin D3, deuterated vitamin D2 or both for 4 weeks. To further investigate the hepatic uptake and hydroxylation of both D-vitamers to 25(OH)D, we conducted cell culture experiments with murine and human hepatoma cells (Hepa1-6 and HepG2). The vitamin D metabolite concentrations in serum, tissues and cells were analyzed by LC-MS/MS or ELISA. In mice, vitamin D2 resulted in lower serum and tissue concentrations of vitamin D (P < 0.001) than vitamin D3, while the group which received both D-vitamers showed values in between. Interestingly, vitamin D2 fed mice had 1.9-times and 2.9-times higher serum concentrations of total and free 25(OH)D (P < 0.001) than mice fed vitamin D3, while the concentration of 1,25-dihydroxyvitamin D (1,25(OH)2D) was 1.8-times lower (P < 0.001). The gene and protein expression of enzymes, involved in the hydroxylation and renal uptake of vitamin D remained largely unaffected by the D-vitamer. In contrast to the mice data, hepatoma cells preferred vitamin D3 for 25-hydroxylation over vitamin D2 (P < 0.001). In general, the formation of 25(OH)D was much more pronounced in human than in murine hepatoma cells (P < 0.001). To conclude, in contrast to humans, vitamin D2 was more efficient in increasing 25(OH)D than vitamin D3 in mice, although this difference was not caused by a preferential hydroxylation of vitamin D2 in the liver. The metabolic routes of D3 and D2 in mice differ, showing lower circulating 1,25(OH)2D and tissue vitamin D concentrations in D2- than in D3-fed mice.
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Affiliation(s)
- Anja C Baur
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Germany.
| | - Corinna Brandsch
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany.
| | - Benita Steinmetz
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany.
| | - Alexandra Schutkowski
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany.
| | - Monika Wensch-Dorendorf
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany.
| | - Gabriele I Stangl
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Germany.
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The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug-Drug Interactions. Pharmaceutics 2020; 12:pharmaceutics12040312. [PMID: 32244748 PMCID: PMC7238003 DOI: 10.3390/pharmaceutics12040312] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 12/13/2022] Open
Abstract
The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (<20% of the total intestinal blood flow) and an inactive serosal region (>80%), were compared to those of the traditional model (TM), wherein 100% of the flow perfuses the non-segregated intestine tissue. The appropriateness of the SFM model is important in terms of drug absorption and intestinal and liver drug metabolism. Model behaviors were examined with respect to intestinally (M1) versus hepatically (M2) formed metabolites and the availabilities in the intestine (FI) and liver (FH) and the route of drug administration. The %contribution of the intestine to total first-pass metabolism bears a reciprocal relation to that for the liver, since the intestine, a gateway tissue, regulates the flow of substrate to the liver. The SFM predicts the highest and lowest M1 formed with oral (po) and intravenous (iv) dosing, respectively, whereas the extent of M1 formation is similar for the drug administered po or iv according to the TM, and these values sit intermediate those of the SFM. The SFM is significant, as this drug metabolism model explains route-dependent intestinal metabolism, describing a higher extent of intestinal metabolism with po versus the much reduced or absence of intestinal metabolism with iv dosing. A similar pattern exists for drug–drug interactions (DDIs). The inhibitor or inducer exerts its greatest effect on victim drugs when both inhibitor/inducer and drug are given po. With po dosing, more drug or inhibitor/inducer is brought into the intestine for DDIs. The bypass of flow and drug to the enterocyte region of the intestine after intravenous administration adds complications to in vitro–in vivo extrapolations (IVIVE).
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Differential Impact of Nevirapine on Artemether-Lumefantrine Pharmacokinetics in Individuals Stratified by CYP2B6 c.516G>T Genotypes. Antimicrob Agents Chemother 2020; 64:AAC.00947-19. [PMID: 31871092 PMCID: PMC7038275 DOI: 10.1128/aac.00947-19] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 12/02/2019] [Indexed: 01/11/2023] Open
Abstract
There is an increased recognition of the need to identify and quantify the impact of genetic polymorphisms on drug-drug interactions. This study investigated the pharmacogenetics of the pharmacokinetic drug-drug interaction between nevirapine and artemether-lumefantrine in HIV-positive and HIV-negative adult Nigerian subjects. There is an increased recognition of the need to identify and quantify the impact of genetic polymorphisms on drug-drug interactions. This study investigated the pharmacogenetics of the pharmacokinetic drug-drug interaction between nevirapine and artemether-lumefantrine in HIV-positive and HIV-negative adult Nigerian subjects. Thirty each of HIV-infected patients on nevirapine-based antiretroviral therapy and HIV-negative volunteers without clinical malaria, but with predetermined CYP2B6 c.516GG and TT genotypes, were administered a complete treatment dose of 3 days of artemether-lumefantrine. Rich pharmacokinetic sampling prior to and following the last dose was conducted, and the plasma concentrations of artemether/dihydroartemisinin and lumefantrine/desbutyl-lumefantrine were quantified using tandem mass spectrometry. Pharmacokinetic parameters of artemether-lumefantrine and its metabolites in HIV-infected patients on nevirapine were compared to those in the absence of nevirapine in HIV-negative volunteers. Overall, nevirapine reduced exposure to artemether and desbutyl-lumefantrine by 39 and 34%, respectively. These reductions were significantly greater in GG versus TT subjects for artemether (ratio of geometric mean [90% confidence interval]: 0.42 [0.29 to 0.61] versus 0.81 [0.51 to 1.28]) and for desbutyl-lumefantrine (0.56 [0.43 to 0.74] versus 0.75 [0.56 to 1.00]). On the contrary, it increased exposure to dihydroartemisinin and lumefantrine by 47 and 30%, respectively. These increases were significantly higher in TT versus GG subjects for dihydroartemisinin (1.67 [1.20 to 2.34] versus 1.25 [0.88 to 1.78]) and for lumefantrine (1.51 [1.20 to 1.90] versus 1.08 [0.82 to 1.42]). This study underscores the importance of incorporating pharmacogenetics into all drug-drug interaction studies with potential for genetic polymorphisms to influence drug disposition.
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Administration of Vitamin D Metabolites Affects RNA Expression of Xenobiotic Metabolising Enzymes and Function of ABC Transporters in Rats. J CHEM-NY 2019. [DOI: 10.1155/2019/1279036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
From studies on different species and in cell culture systems, it has been suggested that vitamin D metabolites might affect the metabolism and elimination of xenobiotics. Although most studies performed on rodents and cell cultures report an upregulation of respective enzymes and transporters, data from the literature are inconsistent. Especially results obtained with sheep differ from these observations. As vitamin D metabolites are widely used as feed additives or therapeutics in livestock animals, we aimed to assess whether these differences indicate species-specific responses or occurred due to the very high dosages used in the rodent studies. Therefore, we applied treatment protocols to rats that had been used previously in sheep or cattle. Forty-eight female rats were divided into three treatment and corresponding placebo groups: (1) a single intraperitoneal injection of 1,25-(OH)2D3 or placebo 12 h before sacrifice; (2) daily supplementation with 25-OHD3 by oral gavage or placebo for 10 days; and (3) a single intramuscular injection of vitamin D3 10 days before sacrifice. In contrast to a previous study using sheep, treatment of rats with 1,25-dihydroxyvitamin D3 did not result in an upregulation of cytochrome P450 3A isoenzymes (CYP3A), but a decrease was found in hepatic and intestinal expressions. In addition, a downregulation of P-glycoprotein (P-gp) and breast cancer resistance protein was found in the brain. Taken together, the stimulating effects of vitamin D metabolites on the expression of genes involved in the metabolism and elimination of xenobiotics reported previously for rodents and sheep could not be reproduced. In contrast, we even observed a negative impact on the expression of CYP3A enzymes and their most important regulator, the pregnane X receptor. Most interestingly, we could demonstrate an effect of treatment with 25-hydroxyvitamin D3 and vitamin D3 on the functional activity of ileal P-glycoprotein (P-gp) using the Ussing chamber technique.
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Akazawa T, Yoshida S, Ohnishi S, Kanazu T, Kawai M, Takahashi K. Application of Intestinal Epithelial Cells Differentiated from Human Induced Pluripotent Stem Cells for Studies of Prodrug Hydrolysis and Drug Absorption in the Small Intestine. Drug Metab Dispos 2018; 46:1497-1506. [PMID: 30135242 DOI: 10.1124/dmd.118.083246] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 08/17/2018] [Indexed: 01/09/2023] Open
Abstract
Cell models to investigate intestinal absorption functions, such as those of transporters and metabolic enzymes, are essential for oral drug discovery and development. The purpose of this study was to generate intestinal epithelial cells from human induced pluripotent stem cells (hiPSC-IECs) and then clarify whether the functions of hydrolase and transporters in them reflect oral drug absorption in the small intestine. The hiPSC-IECs showed the transport activities of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and peptide transporter 1 (PEPT1), revealed by using their probe substrates ([3H]digoxin, sulfasalazine, and [14C]glycylsarcosine), and the metabolic activities of CYP3A4, CES2, and CES1, which were clarified using their probe substrates (midazolam, irinotecan, and temocapril). The intrinsic clearance by hydrolysis of six ester prodrugs into the active form in hiPSC-IECs was correlated with the plasma exposure (Cmax , AUC, and bioavailability) of the active form after oral administration of these prodrugs to rats. Also, the permeability coefficients of 14 drugs, containing two substrates of P-gp (doxorubicin and [3H]digoxin), one substrate of BCRP (sulfasalazine), and 11 nonsubstrates of transporters (ganciclovir, [14C]mannitol, famotidine, sulpiride, atenolol, furosemide, ranitidine, hydrochlorothiazide, acetaminophen, propranolol, and antipyrine) in hiPSC-IECs were correlated with their values of the fraction of intestinal absorption (Fa) in human clinical studies. These findings suggest that hiPSC-IECs would be a useful cell model to investigate the hydrolysis of ester prodrugs and to predict drug absorption in the small intestine.
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Affiliation(s)
- Takanori Akazawa
- Research Laboratory for Development (T.A., S.Y., S.O., T.K.), Medicinal Chemistry Research Laboratory (M.K.), and Drug Discovery and Disease Research Laboratory (K.T.), Shionogi & Co., Ltd, Toyonaka, Osaka, Japan
| | - Shinpei Yoshida
- Research Laboratory for Development (T.A., S.Y., S.O., T.K.), Medicinal Chemistry Research Laboratory (M.K.), and Drug Discovery and Disease Research Laboratory (K.T.), Shionogi & Co., Ltd, Toyonaka, Osaka, Japan
| | - Shuichi Ohnishi
- Research Laboratory for Development (T.A., S.Y., S.O., T.K.), Medicinal Chemistry Research Laboratory (M.K.), and Drug Discovery and Disease Research Laboratory (K.T.), Shionogi & Co., Ltd, Toyonaka, Osaka, Japan
| | - Takushi Kanazu
- Research Laboratory for Development (T.A., S.Y., S.O., T.K.), Medicinal Chemistry Research Laboratory (M.K.), and Drug Discovery and Disease Research Laboratory (K.T.), Shionogi & Co., Ltd, Toyonaka, Osaka, Japan
| | - Makoto Kawai
- Research Laboratory for Development (T.A., S.Y., S.O., T.K.), Medicinal Chemistry Research Laboratory (M.K.), and Drug Discovery and Disease Research Laboratory (K.T.), Shionogi & Co., Ltd, Toyonaka, Osaka, Japan
| | - Koji Takahashi
- Research Laboratory for Development (T.A., S.Y., S.O., T.K.), Medicinal Chemistry Research Laboratory (M.K.), and Drug Discovery and Disease Research Laboratory (K.T.), Shionogi & Co., Ltd, Toyonaka, Osaka, Japan
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Zhang H, Basit A, Busch D, Yabut K, Bhatt DK, Drozdzik M, Ostrowski M, Li A, Collins C, Oswald S, Prasad B. Quantitative characterization of UDP-glucuronosyltransferase 2B17 in human liver and intestine and its role in testosterone first-pass metabolism. Biochem Pharmacol 2018; 156:32-42. [PMID: 30086285 PMCID: PMC6188809 DOI: 10.1016/j.bcp.2018.08.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 08/03/2018] [Indexed: 12/19/2022]
Abstract
Protein abundance and activity of UGT2B17, a highly variable drug- and androgen-metabolizing enzyme, were quantified in microsomes, S9 fractions, and primary cells isolated from human liver and intestine by validated LC-MS/MS methods. UGT2B17 protein abundance showed >160-fold variation (mean ± SD, 1.7 ± 2.7 pmol/mg microsomal protein) in adult human liver microsomes (n = 26) and significant correlation (r2 = 0.77, p < 0.001) with testosterone glucuronide (TG) formation. Primary role of UGT2B17 in TG formation compared to UGT2B15 was confirmed by performing activity assays in UGT2B17 gene deletion samples and with a selective UGT2B17 inhibitor, imatinib. Human intestinal microsomes isolated from small intestine (n = 6) showed on average significantly higher protein abundance (7.4 ± 6.6 pmol/mg microsomal protein, p = 0.016) compared to liver microsomes, with an increasing trend towards distal segments of the gastrointestinal (GI) tract. Commercially available pooled microsomes and S9 fractions confirmed greater abundance and activity of UGT2B17 in intestinal fractions compared to liver fractions. To further investigate the quantitative role of UGT2B17 in testosterone metabolism in whole cell system, a targeted metabolomics study was performed in hepatocytes (n = 5) and enterocytes (n = 16). TG was the second most abundant metabolite after androstenedione in both cell systems. Reasonable correlation between UGT2B17 abundance and activity were observed in enterocytes (r2 = 0.69, p = 0.003), but not in hepatocytes. These observational and mechanistic data will be useful in developing physiologically-based pharmacokinetic (PBPK) models for predicting highly-variable first-pass metabolism of testosterone and other UGT2B17 substrates.
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Affiliation(s)
- Haeyoung Zhang
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
| | - Abdul Basit
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
| | - Diana Busch
- Department of Clinical Pharmacology, University of Greifswald, Greifswald, Germany
| | - King Yabut
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
| | | | - Marek Drozdzik
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland
| | - Marek Ostrowski
- Department of General and Transplantation Surgery, Pomeranian Medical University, Szczecin, Poland
| | - Albert Li
- In Vitro ADMET Laboratories (IVAL), Columbia, MD, USA
| | - Carol Collins
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
| | - Stefan Oswald
- Department of Clinical Pharmacology, University of Greifswald, Greifswald, Germany
| | - Bhagwat Prasad
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
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Basit A, Amory JK, Prasad B. Effect of Dose and 5α-Reductase Inhibition on the Circulating Testosterone Metabolite Profile of Men Administered Oral Testosterone. Clin Transl Sci 2018; 11:513-522. [PMID: 29877607 PMCID: PMC6132360 DOI: 10.1111/cts.12569] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 05/11/2018] [Indexed: 12/16/2022] Open
Abstract
Development of an oral testosterone therapy has proven extremely challenging because of extensive and variable first-pass metabolism. We investigated the in vivo metabolism of testosterone with increasing oral doses of testosterone, both alone and with the co-administration of dutasteride (5α-reductase inhibitor) by liquid-chromatography tandem mass spectrometry (LC-MS/MS). In eugonadal men prior to dosing, the circulating concentration of testosterone, androstenedione, etiocholanolone-glucuronide, and androsterone-glucuronide was 8.6, 20.9, 9.1, and 55.3%, respectively, of the total testosterone-related species, whereas testosterone-glucuronide was ∼1%. When testosterone was dosed orally to men with experimental hypogonadism, a proportion of testosterone-glucuronide increased to 13%. Dutasteride treatment significantly decreased levels of androsterone and its metabolites. This work reveals extensive metabolism of orally dosed testosterone to androsterone glucuronide via androstenedione, with testosterone-glucuronide appearing to be the second most important metabolite. This information is of importance in the development of an effective oral testosterone therapy and may have implications for testosterone doping research.
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Affiliation(s)
- Abdul Basit
- Department of PharmaceuticsUniversity of WashingtonSeattle, WashingtonUSA
| | - John K. Amory
- Department of MedicineUniversity of WashingtonSeattle, WashingtonUSA
| | - Bhagwat Prasad
- Department of PharmaceuticsUniversity of WashingtonSeattle, WashingtonUSA
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11
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Lu W, Rettenmeier E, Paszek M, Yueh MF, Tukey RH, Trottier J, Barbier O, Chen S. Crypt Organoid Culture as an in Vitro Model in Drug Metabolism and Cytotoxicity Studies. Drug Metab Dispos 2017; 45:748-754. [PMID: 28468837 PMCID: PMC5478905 DOI: 10.1124/dmd.117.075945] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 04/27/2017] [Indexed: 12/14/2022] Open
Abstract
The gastrointestinal tract is enriched with xenobiotic processing proteins that play important roles in xenobiotic bioactivation, metabolism, and detoxification. The application of genetically modified mouse models has been instrumental in characterizing the function of xenobiotic processing genes (XPG) and their proteins in drug metabolism. Here, we report the utilization of three-dimensional crypt organoid cultures from these animal models to study intestinal drug metabolism and toxicity. With the successful culturing of crypt organoids, we profiled the abundance of Phase I and Phase II XPG expression, drug transporter gene expression, and xenobiotic nuclear receptor (XNR) gene expression. Functions of XNRs were examined by treating crypt cells with XNR prototypical agonists. Real-time quantitative polymerase chain reaction demonstrated that the representative downstream target genes were induced. These findings were validated from cultures developed from XNR-null mice. In crypt cultures isolated from Pxr-/- mice, pregnenolone 16α-carbonitrile failed to induce Cyp3a11 gene expression; similarly, WY14643 failed to induce Cyp4a10 in the Pparα-/- crypts. Crypt cultures from control (Ugt1F/F ) and intestinal epithelial cell (IEC) specific Ugt1 null mice (Ugt1ΔIEC ) were treated with camptothecin-11, an anticancer prodrug with severe intestinal toxicity that originates from insufficient UGT1A1-dependent glucuronidation of its active metabolite SN-38. In the absence of Ugt1 gene expression, Ugt1ΔIEC crypt cultures exhibit very limited production of SN-38 glucuronide, concordant with increased apoptosis in comparison with Ugt1F/F crypt cultures. This study suggests crypt organoid cultures as an effective in vitro model for studying intestinal drug metabolism and toxicity.
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Affiliation(s)
- Wenqi Lu
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (W.L., E.R., M.P., M-F.Y., R.H.T., S.C.); and Laboratory of Molecular Pharmacology, CHU de Quebec Research Centre and Faculty of Pharmacy, Laval University, Québec (Québec), Canada (J.T., O.B.)
| | - Eva Rettenmeier
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (W.L., E.R., M.P., M-F.Y., R.H.T., S.C.); and Laboratory of Molecular Pharmacology, CHU de Quebec Research Centre and Faculty of Pharmacy, Laval University, Québec (Québec), Canada (J.T., O.B.)
| | - Miles Paszek
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (W.L., E.R., M.P., M-F.Y., R.H.T., S.C.); and Laboratory of Molecular Pharmacology, CHU de Quebec Research Centre and Faculty of Pharmacy, Laval University, Québec (Québec), Canada (J.T., O.B.)
| | - Mei-Fei Yueh
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (W.L., E.R., M.P., M-F.Y., R.H.T., S.C.); and Laboratory of Molecular Pharmacology, CHU de Quebec Research Centre and Faculty of Pharmacy, Laval University, Québec (Québec), Canada (J.T., O.B.)
| | - Robert H Tukey
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (W.L., E.R., M.P., M-F.Y., R.H.T., S.C.); and Laboratory of Molecular Pharmacology, CHU de Quebec Research Centre and Faculty of Pharmacy, Laval University, Québec (Québec), Canada (J.T., O.B.)
| | - Jocelyn Trottier
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (W.L., E.R., M.P., M-F.Y., R.H.T., S.C.); and Laboratory of Molecular Pharmacology, CHU de Quebec Research Centre and Faculty of Pharmacy, Laval University, Québec (Québec), Canada (J.T., O.B.)
| | - Olivier Barbier
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (W.L., E.R., M.P., M-F.Y., R.H.T., S.C.); and Laboratory of Molecular Pharmacology, CHU de Quebec Research Centre and Faculty of Pharmacy, Laval University, Québec (Québec), Canada (J.T., O.B.)
| | - Shujuan Chen
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (W.L., E.R., M.P., M-F.Y., R.H.T., S.C.); and Laboratory of Molecular Pharmacology, CHU de Quebec Research Centre and Faculty of Pharmacy, Laval University, Québec (Québec), Canada (J.T., O.B.)
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12
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Noh K, Oh DG, Nepal MR, Jeong KS, Choi Y, Kang MJ, Kang W, Jeong HG, Jeong TC. Pharmacokinetic Interaction of Chrysin with Caffeine in Rats. Biomol Ther (Seoul) 2016; 24:446-52. [PMID: 27098862 PMCID: PMC4930290 DOI: 10.4062/biomolther.2015.197] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 12/26/2015] [Accepted: 12/29/2015] [Indexed: 11/24/2022] Open
Abstract
Pharmacokinetic interaction of chrysin, a flavone present in honey, propolis and herbs, with caffeine was investigated in male Sprague-Dawley rats. Because chrysin inhibited CYP1A-selective ethoxyresorufin O-deethylase and methoxyresorufin O-demethylase activities in enriched rat liver microsomes, the pharmacokinetics of caffeine, a CYP 1A substrate, was studied following an intragastric administration with 100 mg/kg chrysin. In addition to the oral bioavailability of chrysin, its phase 2 metabolites, chrysin sulfate and chrysin glucuronide, were determined in rat plasma. As results, the pharmacokinetic parameters for caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) were not changed following chrysin treatment in vivo, despite of its inhibitory effect on CYP 1A in vitro. The bioavailability of chrysin was found to be almost zero, because chrysin was rapidly metabolized to its sulfate and glucuronide conjugates in rats. Taken together, it was concluded that the little interaction of chrysin with caffeine might be resulted from the rapid metabolism of chrysin to its phase 2 metabolites which would not have inhibitory effects on CYP enzymes responsible for caffeine metabolism.
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Affiliation(s)
- Keumhan Noh
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Do Gyeong Oh
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Mahesh Raj Nepal
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Ki Sun Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Yongjoo Choi
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Mi Jeong Kang
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Wonku Kang
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Hye Gwang Jeong
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Tae Cheon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
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13
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Schmölz L, Birringer M, Lorkowski S, Wallert M. Complexity of vitamin E metabolism. World J Biol Chem 2016; 7:14-43. [PMID: 26981194 PMCID: PMC4768118 DOI: 10.4331/wjbc.v7.i1.14] [Citation(s) in RCA: 135] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/25/2015] [Accepted: 01/19/2016] [Indexed: 02/05/2023] Open
Abstract
Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e., when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their side-chain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a supplement or nutrient. To evaluate individual vitamin E status, the analytical procedures used for detecting and quantifying vitamin E and its metabolites are crucial. The latest methods in analytics are presented.
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14
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Tydén E, Tjälve H, Larsson P. Gene and protein expression and cellular localisation of cytochrome P450 enzymes of the 1A, 2A, 2C, 2D and 2E subfamilies in equine intestine and liver. Acta Vet Scand 2014; 56:69. [PMID: 25288196 PMCID: PMC4192735 DOI: 10.1186/s13028-014-0069-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 10/03/2014] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Among the cytochrome P450 enzymes (CYP), families 1-3 constitute almost half of total CYPs in mammals and play a central role in metabolism of a wide range of pharmaceuticals. This study investigated gene and protein expression and cellular localisation of CYP1A, CYP2A, CYP2C, CYP2D and CYP2E in equine intestine and liver. Real-time polymerase chain reaction (RT-PCR) was used to analyse gene expression, western blot to examine protein expression and immunohistochemical analyses to investigate cellular localisation. RESULTS CYP1A and CYP2C were the CYPs with the highest gene expression in the intestine and also showed considerable gene expression in the liver. CYP2E and CYP2A showed the highest gene expression in the liver. CYP2E showed moderate intestinal gene expression, whereas that of CYP2A was very low or undetectable. For CYP2D, rather low gene expression levels were found in both intestine and the liver. In the intestine, CYP gene expression levels, except for CYP2E, exhibited patterns resembling those of the proteins, indicating that intestinal protein expression of these CYPs is regulated at the transcriptional level. For CYP2E, the results showed that the intestinal gene expression did not correlate to any visible protein expression, indicating that intestinal protein expression of this CYP is regulated at the post-transcriptional level. Immunostaining of intestine tissue samples showed preferential CYP staining in enterocytes at the tips of intestinal villi in the small intestine. In the liver, all CYPs showed preferential localisation in the centrilobular hepatocytes. CONCLUSIONS Overall, different gene expression profiles were displayed by the CYPs examined in equine intestine and liver. The CYPs present in the intestine may act in concert with those in the liver to affect the oral bioavailability and therapeutic efficiency of substrate drugs. In addition, they may play a role in first-pass metabolism of feed constituents and of herbal supplements used in equine practice.
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Affiliation(s)
- Eva Tydén
- Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden
| | - Hans Tjälve
- Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden
| | - Pia Larsson
- Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden
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15
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Contributions of Intestine and Plasma to the Presystemic Bioconversion of Vicagrel, an Acetate of Clopidogrel. Pharm Res 2013; 31:238-51. [DOI: 10.1007/s11095-013-1158-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Accepted: 07/22/2013] [Indexed: 02/05/2023]
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16
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Qiu Z, Li N, Wang X, Tian F, Liu Q, Song L, Fan Z, Lu Y, Chen X. Pharmacokinetics of Vicagrel, a Promising Analog of Clopidogrel, in Rats and Beagle Dogs. J Pharm Sci 2013. [DOI: 10.1002/jps.23394] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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17
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Kuze J, Mutoh T, Takenaka T, Oda N, Hanioka N, Narimatsu S. Evaluation of animal models for intestinal first-pass metabolism of drug candidates to be metabolized by CYP3A enzymes via in vivo and in vitro oxidation of midazolam and triazolam. Xenobiotica 2013; 43:598-606. [PMID: 23282066 DOI: 10.3109/00498254.2012.751517] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
1. To search an appropriate evaluation methodology for the intestinal first-pass metabolism of new drug candidates, grapefruit juice (GFJ)- and vehicle (tap water)-pretreated mice or rats were orally administered midazolam (MDZ) or triazolam (TRZ), and blood levels of the parent compounds and their metabolites were measured by liquid chromatography/MS/MS. A significant effect of GFJ to elevate the blood levels was observed only for TRZ in mice. 2. In vitro experiments using mouse, rat and human intestinal and hepatic microsomal fractions demonstrated that GFJ suppressed the intestinal microsomal oxidation of MDZ and especially TRZ. Substrate inhibition by MDZ caused reduction in 1'-hydroxylation but not 4-hydroxylation in both intestinal and hepatic microsomal fractions. The kinetic profiles of MDZ oxidation and the substrate inhibition in mouse intestinal and hepatic microsomal fractions were very similar to those in human microsomes but were different from those in rat microsomes. Furthermore, MDZ caused mechanism-based inactivation of cytochrome P450 3A-dependent TRZ 1'-hydroxylation in mouse, rat and human intestinal microsomes with similar potencies. 3. These results are useful information in the analysis of data obtained in mouse and rat for the evaluation of first-pass effects of drug candidates to be metabolized by CYP3A enzymes.
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Affiliation(s)
- J Kuze
- Tsukuba Research Center, Taiho Pharmaceutical Company, Ibaraki, Japan
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Cho SM, Park SW, Kim NH, Park JA, Yi H, Cho HJ, Park KH, Hwang I, Shin HC. Expression of intestinal transporter genes in beagle dogs. Exp Ther Med 2012; 5:308-314. [PMID: 23251289 PMCID: PMC3524273 DOI: 10.3892/etm.2012.777] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 10/12/2012] [Indexed: 11/06/2022] Open
Abstract
This study was performed to produce a transcriptional database of the intestinal transporters of beagle dogs. Total RNA was isolated from the duodenum and the expression of various mRNAs was measured using GeneChip(®) oligonucleotide arrays. A total of 124 transporter genes were detected. Genes for fatty acid, peptide, amino acid and glucose and multidrug resistance/multidrug resistance-associated protein (MDR/MRP) transport were expressed at relatively higher levels than the other transporter types. The dogs exhibited abundant mRNA expression of the fatty acid transporters (fatty acid binding proteins, FABPs) FABP1 and FABP2, the ATP-binding cassettes (ABCs) ABCB1A and ABCC2, the amino acid/peptide transporters SLC3A1 and SLC15A1, the glucose transporters SLC5A1, SLC2A2 and SLC2A5, the organic anion transporter SLC22A9 and the phosphate transporters SLC20A1 and SLC37A4. In mice, a similar profile was observed with high expression of the glucose transporters SLC5A1 and SLC2As, the fatty acid transporters FABP1 and FABP2, the MDR/MRP transporters ABCB1A and ABCC2 and the phosphate transporter SLC37A4. However, the overall data reveal diverse transcriptomic profiles of the intestinal transporters of dogs and mice. Therefore, the current database may be useful for comparing the intestinal transport systems of dogs with those of mice to better evaluate xenobiotics.
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Affiliation(s)
- Soo-Min Cho
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, Seoul 143-701
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Bardowell SA, Ding X, Parker RS. Disruption of P450-mediated vitamin E hydroxylase activities alters vitamin E status in tocopherol supplemented mice and reveals extra-hepatic vitamin E metabolism. J Lipid Res 2012; 53:2667-76. [PMID: 22969154 DOI: 10.1194/jlr.m030734] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The widely conserved preferential accumulation of α-tocopherol (α-TOH) in tissues occurs, in part, from selective postabsorptive catabolism of non-α-TOH forms via the vitamin E-ω-oxidation pathway. We previously showed that global disruption of CYP4F14, the major but not the only mouse TOH-ω-hydroxylase, resulted in hyper-accumulation of γ-TOH in mice fed a soybean oil diet. In the current study, supplementation of Cyp4f14(-/-) mice with high levels of δ- and γ-TOH exacerbated tissue enrichment of these forms of vitamin E. However, at high dietary levels of TOH, mechanisms other than ω-hydroxylation dominate in resisting diet-induced accumulation of non-α-TOH. These include TOH metabolism via ω-1/ω-2 oxidation and fecal elimination of unmetabolized TOH. The ω-1 and ω-2 fecal metabolites of γ- and α-TOH were observed in human fecal material. Mice lacking all liver microsomal CYP activity due to disruption of cytochrome P450 reductase revealed the presence of extra-hepatic ω-, ω-1, and ω-2 TOH hydroxylase activities. TOH-ω-hydroxylase activity was exhibited by microsomes from mouse and human small intestine; murine activity was entirely due to CYP4F14. These findings shed new light on the role of TOH-ω-hydroxylase activity and other mechanisms in resisting diet-induced accumulation of tissue TOH and further characterize vitamin E metabolism in mice and humans.
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Peltoniemi MA, Saari TI, Hagelberg NM, Laine K, Kurkinen KJ, Neuvonen PJ, Olkkola KT. Rifampicin has a Profound Effect on the Pharmacokinetics of Oral S-Ketamine and Less on Intravenous S-Ketamine. Basic Clin Pharmacol Toxicol 2012; 111:325-32. [DOI: 10.1111/j.1742-7843.2012.00908.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 05/23/2012] [Indexed: 10/24/2022]
Affiliation(s)
- Marko A. Peltoniemi
- Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine; University of Turku and Turku University Hospital; Turku Finland
| | - Teijo I. Saari
- Department of Anesthesiology; Friedrich-Alexander University Erlangen-Nuremberg; Erlangen Germany
| | - Nora M. Hagelberg
- Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine; University of Turku and Turku University Hospital; Turku Finland
| | - Kari Laine
- Department of Pharmacology, Drug Development and Therapeutics; University of Turku; Turku Finland
| | - Kaisa J. Kurkinen
- Department of Clinical Pharmacology; University of Helsinki and HUSLAB; Helsinki University Central Hospital; Helsinki Finland
| | - Pertti J. Neuvonen
- Department of Clinical Pharmacology; University of Helsinki and HUSLAB; Helsinki University Central Hospital; Helsinki Finland
| | - Klaus T. Olkkola
- Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine; University of Turku and Turku University Hospital; Turku Finland
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Hasegawa M, Tahara H, Inoue R, Kakuni M, Tateno C, Ushiki J. Investigation of drug-drug interactions caused by human pregnane X receptor-mediated induction of CYP3A4 and CYP2C subfamilies in chimeric mice with a humanized liver. Drug Metab Dispos 2012; 40:474-80. [PMID: 22126990 DOI: 10.1124/dmd.111.042754] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
The induction of cytochrome P450 (P450) enzymes is one of the risk factors for drug-drug interactions (DDIs). To date, the human pregnane X receptor (PXR)-mediated CYP3A4 induction has been well studied. In addition to CYP3A4, the expression of CYP2C subfamily is also regulated by PXR, and the DDIs caused by the induction of CYP2C enzymes have been reported to have a major clinical impact. The purpose of the present study was to investigate whether chimeric mice with a humanized liver (PXB mice) can be a suitable animal model for investigating the PXR-mediated induction of CYP2C subfamily, together with CYP3A4. We evaluated the inductive effect of rifampicin (RIF), a typical human PXR ligand, on the plasma exposure to the four P450 substrate drugs (triazolam/CYP3A4, pioglitazone/CYP2C8, (S)-warfarin/CYP2C9, and (S)-(-)-mephenytoin/CYP2C19) by cassette dosing in PXB mice. The induction of several drug-metabolizing enzymes and transporters in the liver was also examined by measuring the enzyme activity and mRNA expression levels. Significant reductions in the exposure to triazolam, pioglitazone, and (S)-(-)-mephenytoin, but not to (S)-warfarin, were observed. In contrast to the in vivo results, all the four P450 isoforms, including CYP2C9, were elevated by RIF treatment. The discrepancy in the (S)-warfarin results between in vivo and in vitro studies may be attributed to the relatively small contribution of CYP2C9 to (S)-warfarin elimination in the PXB mice used in this study. In summary, PXB mice are a useful animal model to examine DDIs caused by PXR-mediated induction of CYP2C and CYP3A4.
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Affiliation(s)
- Maki Hasegawa
- Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan.
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