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Malavé JG, Lopez A, Doan T, Cicali EJ, Desta Z, McDonough CW, Cavallari LH. Evaluating the Evidence for CYP2C19 Inhibitor Classifications: A Scoping Review. Clin Pharmacol Ther 2025. [PMID: 40391533 DOI: 10.1002/cpt.3712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/25/2025] [Indexed: 05/21/2025]
Abstract
The Food and Drug Administration (FDA) Table of Inhibitors and the Flockhart Table™ are important references for identifying CYP2C19 inhibitors. Accurate inhibitor classification is essential for evaluating phenoconversion and managing drug-drug interactions. The objective of this study was to assess the concordance between inhibitor classifications according to the FDA and Flockhart tables and pharmacokinetic data from the primary literature. A scoping review of PubMed, product labels, and the Drug Interactions Database (DIDB®) up to April 2024 was conducted. Inhibitor-substrate pairs (e.g., fluoxetine-omeprazole) were assigned literature-reported classifications (i.e., weak, moderate, or strong) based on pharmacokinetic data. Concordance between literature-reported and listed classifications was evaluated. Of 90 inhibitor-substrate pairs identified, 66% involved sensitive substrates, which were the focus of our primary analysis. Among sensitive inhibitor-substrate pairs, 36% of FDA-listed and 45% of Flockhart-listed classifications were concordant with the literature. CYP2C19 phenotype appeared to impact concordance, with greater concordance among normal metabolizers for both FDA-listed (42%) and Flockhart-listed (50%) classifications. Steady state status and dosing also appeared to affect concordance. Discrepancies between listed and literature-reported classifications led to the following recommendations: (1) upgrade fluoxetine from moderate to strong in the Flockhart Table™, (2) upgrade fluconazole from moderate to strong in the Flockhart Table™, (3) downgrade omeprazole (and esomeprazole) from moderate to weak in the Flockhart Table™, and (4) include footnotes describing dose-dependent inhibition for fluvoxamine and fluconazole in both tables. These recommendations aim to improve the accuracy of CYP2C19 inhibitor classifications and the clinical utility of these tables.
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Affiliation(s)
- Jean G Malavé
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| | - Andrés Lopez
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| | - Thi Doan
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| | - Emily J Cicali
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| | - Zeruesenay Desta
- Division of Clinical Pharmacology, Indiana University, School of Medicine, Indianapolis, Indiana, USA
| | - Caitrin W McDonough
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| | - Larisa H Cavallari
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA
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Wang L, Chen L, Yao Y, Shen H, Xu Y. A Mechanism Study on the (+)-ESI-TOF/HRMS Fragmentation of Some PPI Prazoles and Their Related Substances. Molecules 2023; 28:5852. [PMID: 37570821 PMCID: PMC10420917 DOI: 10.3390/molecules28155852] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/09/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
Fragmentation mechanisms of some prazoles and their related substances were newly investigated in this paper via positive mode ESI-TOF HRMS1 and HRMS2. Some novel fragmentation rules or ions were found or detected in the research. The pyridine and the benzoimidazole ring remained in most cases during the ionization, and heterolytic fragmentations often occurred near the -S(O)nCH2- linker to give the [1,3]-H migration ion or [1,7]-H migration ion rearranging across the benzoimdazole ring. Smiles rearrangement ionizations also frequently occurred, initiated by the attack of the lone pair electrons from the pyridine ring, and the sulfones gave special N-(2-benzoimdazolyl) pyridine ions (11b and 12c) by a direct extraction from SO2, and the thioethers gave similar framework ions (8c, 9c and 10c) via the rearrangement and a further homolytic cleavage of SH radicals. However, the sulfoxides were seldom detected in the corresponding Smiles rearrangement ions during our measurement, and the N'-oxides of the pyridines did not undergo the Smiles rearrangement ionization due to the absence of the lone pair electrons. The 5/6-membered chelating ions with Na+ or K+ were frequently detected as the molecular and further fragment ions. Some novel and interesting fragment ions containing bivalent (8b and 9b), tetravalent (4b, 5c and 6c) or hexavalent (15b and 16b) sulfurs were first reported here.
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Affiliation(s)
| | | | | | - Hongyan Shen
- Key Laboratory of Structure-Based Drug Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; (L.W.); (L.C.); (Y.Y.)
| | - Youjun Xu
- Key Laboratory of Structure-Based Drug Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; (L.W.); (L.C.); (Y.Y.)
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Ho TT, Noble M, Tran BA, Sunjic K, Gupta SV, Turgeon J, Crutchley RD. Clinical Impact of the CYP2C19 Gene on Diazepam for the Management of Alcohol Withdrawal Syndrome. J Pers Med 2023; 13:jpm13020285. [PMID: 36836519 PMCID: PMC9961427 DOI: 10.3390/jpm13020285] [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: 12/30/2022] [Revised: 01/26/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Diazepam is a benzodiazepine widely prescribed for the management of patients with severe alcohol withdrawal syndrome to prevent agitation, withdrawal seizures, and delirium tremens. Despite standard dosing of diazepam, a subset of patients experience refractory withdrawal syndromes or adverse drug reactions, such as impaired motor coordination, dizziness, and slurred speech. The CYP2C19 and CYP3A4 enzymes play a key role in the biotransformation of diazepam. Given the highly polymorphic nature of the CYP2C19 gene, we reviewed the clinical impact of variants in the CYP2C19 gene on both the pharmacokinetics of diazepam and treatment outcomes related to the management of alcohol withdrawal syndrome.
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Affiliation(s)
- Teresa T. Ho
- Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA
- Correspondence:
| | - Melissa Noble
- Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA
| | - Bao Anh Tran
- Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA
| | - Katlynd Sunjic
- Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA
| | - Sheeba Varghese Gupta
- Department of Pharmaceutical Sciences, University of South Florida College of Pharmacy, Tampa, FL 33612, USA
| | - Jacques Turgeon
- Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA
| | - Rustin D. Crutchley
- Department of Pharmacotherapy, Washington State University, College of Pharmacy and Pharmaceutical Sciences, Yakima, WA 98901, USA
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Optimising Seniors' Metabolism of Medications and Avoiding Adverse Drug Events Using Data on How Metabolism by Their P450 Enzymes Varies with Ancestry and Drug-Drug and Drug-Drug-Gene Interactions. J Pers Med 2020; 10:jpm10030084. [PMID: 32796505 PMCID: PMC7563167 DOI: 10.3390/jpm10030084] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/01/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Many individuals ≥65 have multiple illnesses and polypharmacy. Primary care physicians prescribe >70% of their medications and renew specialists’ prescriptions. Seventy-five percent of all medications are metabolised by P450 cytochrome enzymes. This article provides unique detailed tables how to avoid adverse drug events and optimise prescribing based on two key databases. DrugBank is a detailed database of 13,000 medications and both the P450 and other complex pathways that metabolise them. The Flockhart Tables are detailed lists of the P450 enzymes and also include all the medications which inhibit or induce metabolism by P450 cytochrome enzymes, which can result in undertreatment, overtreatment, or potentially toxic levels. Humans have used medications for a few decades and these enzymes have not been subject to evolutionary pressure. Thus, there is enormous variation in enzymatic functioning and by ancestry. Differences for ancestry groups in genetic metabolism based on a worldwide meta-analysis are discussed and this article provides advice how to prescribe for individuals of different ancestry. Prescribing advice from two key organisations, the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium is summarised. Currently, detailed pharmacogenomic advice is only available in some specialist clinics in major hospitals. However, this article provides detailed pharmacogenomic advice for primary care and other physicians and also physicians working in rural and remote areas worldwide. Physicians could quickly search the tables for the medications they intend to prescribe.
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Liu A, Jubran B, Enwere EK, Hansen M, Burma NE, Nasser Y. Acid Suppressive Therapy. ENCYCLOPEDIA OF GASTROENTEROLOGY 2020:18-31. [DOI: 10.1016/b978-0-12-801238-3.65617-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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6
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Ortiz-Guerrero G, Amador-Muñoz D, Calderón-Ospina CA, López-Fuentes D, Nava Mesa MO. Proton Pump Inhibitors and Dementia: Physiopathological Mechanisms and Clinical Consequences. Neural Plast 2018; 2018:5257285. [PMID: 29755512 PMCID: PMC5883984 DOI: 10.1155/2018/5257285] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 02/14/2018] [Indexed: 12/11/2022] Open
Abstract
Alzheimer's disease (AD) is the most common type of dementia, mainly encompassing cognitive decline in subjects aged ≥65 years. Further, AD is characterized by selective synaptic and neuronal degeneration, vascular dysfunction, and two histopathological features: extracellular amyloid plaques composed of amyloid beta peptide (Aβ) and neurofibrillary tangles formed by hyperphosphorylated tau protein. Dementia and AD are chronic neurodegenerative conditions with a complex physiopathology involving both genetic and environmental factors. Recent clinical studies have shown that proton pump inhibitors (PPIs) are associated with risk of dementia, including AD. However, a recent case-control study reported decreased risk of dementia. PPIs are a widely indicated class of drugs for gastric acid-related disorders, although most older adult users are not treated for the correct indication. Although neurological side effects secondary to PPIs are rare, several preclinical reports indicate that PPIs might increase Aβ levels, interact with tau protein, and affect the neuronal microenvironment through several mechanisms. Considering the controversy between PPI use and dementia risk, as well as both cognitive and neuroprotective effects, the aim of this review is to examine the relationship between PPI use and brain effects from a neurobiological and clinical perspective.
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Affiliation(s)
- Gloria Ortiz-Guerrero
- Individualized Research Learner Program, Neuromuscular Research Division, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Diana Amador-Muñoz
- Neuroscience (NEUROS) Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C–69, Bogotá 111221, Colombia
| | - Carlos Alberto Calderón-Ospina
- Unidad de Farmacología, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C–69, Bogotá 111221, Colombia
| | - Daniel López-Fuentes
- Medical Social Service, Hospital de San Francisco, Kra 8 No. 6A–121, Gacheta 251230, Colombia
| | - Mauricio Orlando Nava Mesa
- Neuroscience (NEUROS) Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C–69, Bogotá 111221, Colombia
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Bahar MA, Setiawan D, Hak E, Wilffert B. Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6. Pharmacogenomics 2017; 18:701-739. [PMID: 28480783 DOI: 10.2217/pgs-2017-0194] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Currently, most guidelines on drug-drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug-gene interaction (DGI) where there are multiple biotransformation pathways, which is referred to as drug-drug-gene interaction (DDGI). In this systematic review, we report the impact of pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes - CYP2C9, CYP2C19 and CYP2D6 - are central. We observed that several DDI and DDGI are highly gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take pharmacogenetics into account when drug interactions in clinical practice are expected.
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Affiliation(s)
- Muh Akbar Bahar
- Department of PharmacoTherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.,Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | - Didik Setiawan
- Department of PharmacoTherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.,Faculty of Pharmacy, University of Muhammadiyah Purwokerto, Purwokerto, Indonesia
| | - Eelko Hak
- Department of PharmacoTherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Bob Wilffert
- Department of PharmacoTherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.,Department of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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8
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Furuta T, Sugimoto M, Kodaira C, Nishino M, Yamade M, Uotani T, Sahara S, Ichikawa H, Kagami T, Iwaizumi M, Hamaya Y, Osawa S, Sugimoto K, Umemura K. Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel. J Thromb Thrombolysis 2017; 43:333-342. [PMID: 27981489 DOI: 10.1007/s11239-016-1460-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 ± 21.1%, 43.2 ± 20.2%, 46.4 ± 18.8%, and 47.3 ± 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps < 0.001). This decrease was observed when PPIs were administered separately in the evening. However, IPA by clopidogrel with rabeprazole administered at lunchtime was 51.6%, which was markedly similar to that of clopidogrel alone (p = 0.114). All tested PPIs reduce the efficacy of clopidogrel when administered concomitantly. Our preliminary data suggest that administration of rabeprazole 4 h following clopidogrel may minimize potential drug-drug interactions.
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Affiliation(s)
- Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Shizuoka, Japan.
| | - Mitsushige Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Chise Kodaira
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Masafumi Nishino
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Mihoko Yamade
- Department of Clinical Oncology, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takahiro Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Shu Sahara
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Hitomi Ichikawa
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takuma Kagami
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Moriya Iwaizumi
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Kazuo Umemura
- Department of Pharmacology, Hamamatsu University School of Medicine, Shizuoka, Japan
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9
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Abstract
Proton pump inhibitors (PPIs) are used extensively for the treatment of gastric acid-related disorders, often over the long term, which raises the potential for clinically significant drug interactions in patients receiving concomitant medications. These drug–drug interactions have been previously reviewed. However, the current knowledge is likely to have advanced, so a thorough review of the literature published since 2006 was conducted. This identified new studies of drug interactions that are modulated by gastric pH. These studies showed the effect of a PPI-induced increase in intragastric pH on mycophenolate mofetil pharmacokinetics, which were characterised by a decrease in the maximum exposure and availability of mycophenolic acid, at least at early time points. Post-2006 data were also available outlining the altered pharmacokinetics of protease inhibitors with concomitant PPI exposure. New data for the more recently marketed dexlansoprazole suggest it has no impact on the pharmacokinetics of diazepam, phenytoin, theophylline and warfarin. The CYP2C19-mediated interaction that seems to exist between clopidogrel and omeprazole or esomeprazole has been shown to be clinically important in research published since the 2006 review; this effect is not seen as a class effect of PPIs. Finally, data suggest that coadministration of PPIs with methotrexate may affect methotrexate pharmacokinetics, although the mechanism of interaction is not well understood. As was shown in the previous review, individual PPIs differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole sodium (pantoprazole-Na) have been studied most extensively. Several studies have shown that omeprazole carries a considerable potential for drug interactions because of its high affinity for CYP2C19 and moderate affinity for CYP3A4. In contrast, pantoprazole-Na appears to have lower potential for interactions with other medications. Lansoprazole and rabeprazole also seem to have a weaker potential for interactions than omeprazole, although their interaction profiles, along with those of esomeprazole and dexlansoprazole, have been less extensively investigated. Only a few drug interactions involving PPIs are of clinical significance. Nonetheless, the potential for drug interactions should be considered when choosing a PPI to manage gastric acid-related disorders. This is particularly relevant for elderly patients taking multiple medications, or for those receiving a concomitant medication with a narrow therapeutic index.
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Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol Ther 2014; 95:653-62. [PMID: 24569517 PMCID: PMC4029899 DOI: 10.1038/clpt.2014.50] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 02/14/2014] [Indexed: 01/14/2023]
Abstract
Fluoxetine and its circulating metabolite norfluoxetine comprise a complex multiple-inhibitor system that causes reversible or time-dependent inhibition of the cytochrome P450 (CYP) family members CYP2D6, CYP3A4, and CYP2C19 in vitro. Although significant inhibition of all three enzymes in vivo was predicted, the areas under the concentration-time curve (AUCs) for midazolam and lovastatin were unaffected by 2-week dosing of fluoxetine, whereas the AUCs of dextromethorphan and omeprazole were increased by 27- and 7.1-fold, respectively. This observed discrepancy between in vitro risk assessment and in vivo drug-drug interaction (DDI) profile was rationalized by time-varying dynamic pharmacokinetic models that incorporated circulating concentrations of fluoxetine and norfluoxetine enantiomers, mutual inhibitor-inhibitor interactions, and CYP3A4 induction. The dynamic models predicted all DDIs with less than twofold error. This study demonstrates that complex DDIs that involve multiple mechanisms, pathways, and inhibitors with their metabolites can be predicted and rationalized via characterization of all the inhibitory species in vitro.
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Affiliation(s)
- J E Sager
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA
| | - J D Lutz
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA
| | - R S Foti
- Department of Pharmacokinetics and Drug Metabolism, Amgen, Seattle, Washington, USA
| | - C Davis
- Division of Nephrology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, USA
| | - K L Kunze
- Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, USA
| | - N Isoherranen
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA
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11
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Functional polymorphisms in the CYP2C19 gene contribute to digestive system cancer risk: evidence from 11,042 subjects. PLoS One 2013; 8:e66865. [PMID: 23874401 PMCID: PMC3712993 DOI: 10.1371/journal.pone.0066865] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 05/12/2013] [Indexed: 12/19/2022] Open
Abstract
Background CYP2C19 belongs to the cytochrome P450 superfamily of enzymes involved in activating and detoxifying many carcinogens and endogenous compounds, which has attracted considerable attention as a candidate gene for digestive system cancer. CYP2C19 has two main point mutation sites (CYP2C19*2, CYP2C19*3) leading to poor metabolizer (PM) phenotype. In the past decade, the relationship between CYP2C19 polymorphism and digestive system cancer has been reported in various ethnic groups; however, these studies have yielded contradictory results. Methods To clarify this inconsistency, we performed this meta-analysis. Databases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Results In total, 18 studies with 4,414 cases and 6,628 controls were included. Overall, significantly elevated digestive system cancer risk was associated CYP2C19 PM with OR of 1.66 (95%CI: 1.31–2.10, P<10−5) when all studies were pooled into the meta-analysis. There was strong evidence of heterogeneity (P = 0.006), which largely disappeared after stratification by cancer type. In the stratified analyses according to cancer type, ethnicity, control source and sample size, significantly increased risks were found. Conclusions In summary, our meta-analysis suggested that the PM phenotype caused by the variation on CYP2C19 gene is associated with increased risk of digestive system cancer, especially in East Asians.
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12
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Shirasaka Y, Sager JE, Lutz JD, Davis C, Isoherranen N. Inhibition of CYP2C19 and CYP3A4 by omeprazole metabolites and their contribution to drug-drug interactions. Drug Metab Dispos 2013; 41:1414-24. [PMID: 23620487 PMCID: PMC3684819 DOI: 10.1124/dmd.113.051722] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Accepted: 04/25/2013] [Indexed: 01/21/2023] Open
Abstract
The aim of this study was to evaluate the contribution of metabolites to drug-drug interactions (DDI) using the inhibition of CYP2C19 and CYP3A4 by omeprazole and its metabolites as a model. Of the metabolites identified in vivo, 5-hydroxyomeprazole, 5'-O-desmethylomeprazole, omeprazole sulfone, and carboxyomeprazole had a metabolite to parent area under the plasma concentration-time curve (AUC(m)/AUC(p)) ratio ≥ 0.25 when either total or unbound concentrations were measured after a single 20-mg dose of omeprazole in a cocktail. All of the metabolites inhibited CYP2C19 and CYP3A4 reversibly. In addition omeprazole, omeprazole sulfone, and 5'-O-desmethylomeprazole were time dependent inhibitors (TDI) of CYP2C19, whereas omeprazole and 5'-O-desmethylomeprazole were found to be TDIs of CYP3A4. The in vitro inhibition constants and in vivo plasma concentrations were used to evaluate whether characterization of the metabolites affected DDI risk assessment. Identifying omeprazole as a TDI of both CYP2C19 and CYP3A4 was the most important factor in DDI risk assessment. Consideration of reversible inhibition by omeprazole and its metabolites would not identify DDI risk with CYP3A4, and with CYP2C19, reversible inhibition values would only identify DDI risk if the metabolites were included in the assessment. On the basis of inactivation data, CYP2C19 and CYP3A4 inhibition by omeprazole would be sufficient to identify risk, but metabolites were predicted to contribute 30-63% to the in vivo hepatic interactions. Therefore, consideration of metabolites may be important in quantitative predictions of in vivo DDIs. The results of this study show that, although metabolites contribute to in vivo DDIs, their relative abundance in circulation or logP values do not predict their contribution to in vivo DDI risk.
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Affiliation(s)
- Yoshiyuki Shirasaka
- Department of Pharmaceutics, School of Pharmacy, University of Washington, University of Washington, Seattle, WA, USA
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13
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Li W, Zeng S, Yu LS, Zhou Q. Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management. Ther Clin Risk Manag 2013; 9:259-71. [PMID: 23745048 PMCID: PMC3671798 DOI: 10.2147/tcrm.s43151] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Omeprazole, a proton pump inhibitor (PPI), is widely used for the treatment of dyspepsia, peptic ulcer, gastroesophageal reflux disease, and functional dyspepsia. Polypharmacy is common in patients receiving omeprazole. Drug toxicity and treatment failure resulting from inappropriate combination therapy with omeprazole have been reported sporadically. Systematic review has not been available to address the pharmacokinetic drug-drug interaction (DDI) profile of omeprazole with adverse consequences, the factors determining the degree of DDI between omeprazole and comedication, and the corresponding clinical risk management. METHODS Literature was identified by performing a PubMed search covering the period from January 1988 to March 2013. The full text of each article was critically reviewed, and data interpretation was performed. RESULTS Omeprazole has actual adverse influences on the pharmacokinetics of medications such as diazepam, carbamazepine, clozapine, indinavir, nelfinavir, atazanavir, rilpivirine, methotrexate, tacrolimus, mycophenolate mofetil, clopidogrel, digoxin, itraconazole, posaconazole, and oral iron supplementation. Meanwhile, low efficacy of omeprazole treatment would be anticipated, as omeprazole elimination could be significantly induced by comedicated efavirenz and herb medicines such as St John's wort, Ginkgo biloba, and yin zhi huang. The mechanism for DDI involves induction or inhibition of cytochrome P450, inhibition of P-glycoprotein or breast cancer resistance protein-mediated drug transport, and inhibition of oral absorption by gastric acid suppression. Sometimes, DDIs of omeprazole do not exhibit a PPI class effect. Other suitable PPIs or histamine 2 antagonists may be therapeutic alternatives that can be used to avoid adverse consequences. The degree of DDIs associated with omeprazole and clinical outcomes depend on factors such as genotype status of CYP2C19 and CYP1A2, ethnicity, dose and treatment course of precipitant omeprazole, pharmaceutical formulation of object drug (eg, mycophenolate mofetil versus enteric-coated mycophenolate sodium), other concomitant medication (eg, omeprazole-indinavir versus omeprazole-indinavir-ritonavir), and administration schedule (eg, intensified dosing of mycophenolate mofetil versus standard dosing). CONCLUSION Despite the fact that omeprazole is one of the most widely prescribed drugs internationally, clinical professionals should enhance clinical risk management on adverse DDIs associated with omeprazole and ensure safe combination use of omeprazole by rationally prescribing alternatives, checking the appropriateness of physician orders before dispensing, and performing therapeutic drug monitoring.
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Affiliation(s)
- Wei Li
- Division of Medical Affairs, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
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14
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Isoherranen N, Lutz JD, Chung SP, Hachad H, Levy RH, Ragueneau-Majlessi I. Importance of multi-p450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude, and prediction from in vitro data. Chem Res Toxicol 2012; 25:2285-300. [PMID: 22823924 PMCID: PMC3502654 DOI: 10.1021/tx300192g] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Drugs that are mainly cleared by a single enzyme are considered more sensitive to drug-drug interactions (DDIs) than drugs cleared by multiple pathways. However, whether this is true when a drug cleared by multiple pathways is coadministered with an inhibitor of multiple P450 enzymes (multi-P450 inhibition) is not known. Mathematically, simultaneous equipotent inhibition of two elimination pathways that each contribute half of the drug clearance is equal to equipotent inhibition of a single pathway that clears the drug. However, simultaneous strong or moderate inhibition of two pathways by a single inhibitor is perceived as an unlikely scenario. The aim of this study was (i) to identify P450 inhibitors currently in clinical use that can inhibit more than one clearance pathway of an object drug in vivo and (ii) to evaluate the magnitude and predictability of DDIs caused by these multi-P450 inhibitors. Multi-P450 inhibitors were identified using the Metabolism and Transport Drug Interaction Database. A total of 38 multi-P450 inhibitors, defined as inhibitors that increased the AUC or decreased the clearance of probes of two or more P450s, were identified. Seventeen (45%) multi-P450 inhibitors were strong inhibitors of at least one P450, and an additional 12 (32%) were moderate inhibitors of one or more P450s. Only one inhibitor (fluvoxamine) was a strong inhibitor of more than one enzyme. Fifteen of the multi-P450 inhibitors also inhibit drug transporters in vivo, but such data are lacking on many of the inhibitors. Inhibition of multiple P450 enzymes by a single inhibitor resulted in significant (>2-fold) clinical DDIs with drugs that are cleared by multiple pathways such as imipramine and diazepam, while strong P450 inhibitors resulted in only weak DDIs with these object drugs. The magnitude of the DDIs between multi-P450 inhibitors and diazepam, imipramine, and omeprazole could be predicted using in vitro data with similar accuracy as probe substrate studies with the same inhibitors. The results of this study suggest that inhibition of multiple clearance pathways in vivo is clinically relevant, and the risk of DDIs with object drugs may be best evaluated in studies using multi-P450 inhibitors.
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Affiliation(s)
- Nina Isoherranen
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Box 357610, Seattle, WA 98195, USA.
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15
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Zvyaga T, Chang SY, Chen C, Yang Z, Vuppugalla R, Hurley J, Thorndike D, Wagner A, Chimalakonda A, Rodrigues AD. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos 2012; 40:1698-711. [PMID: 22648560 DOI: 10.1124/dmd.112.045575] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Six proton pump inhibitors (PPIs), omeprazole, lansoprazole, esomeprazole, dexlansoprazole, pantoprazole, and rabeprazole, were shown to be weak inhibitors of cytochromes P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2) in human liver microsomes. In most cases, IC₅₀ values were greater than 40 μM, except for dexlansoprazole and lansoprazole with CYP1A2 (IC₅₀ = ∼8 μM) and esomeprazole with CYP2C8 (IC₅₀ = 31 μM). With the exception of CYP2C19 inhibition by omeprazole and esomeprazole (IC₅₀ ratio, 2.5 to 5.9), there was no evidence for a marked time-dependent shift in IC₅₀ (IC₅₀ ratio, ≤ 2) after a 30-min preincubation with NADPH. In the absence of preincubation, lansoprazole (IC₅₀ = 0.73 μM) and esomeprazole (IC₅₀ = 3.7 μM) were the most potent CYP2C19 inhibitors, followed by dexlansoprazole and omeprazole (IC₅₀ = ∼7.0 μM). Rabeprazole and pantoprazole (IC₅₀ = ≥ 25 μM) were the weakest. A similar ranking was obtained with recombinant CYP2C19. Despite the IC₅₀ ranking, after consideration of plasma levels (static and dynamic), protein binding, and metabolism-dependent inhibition, it is concluded that omeprazole and esomeprazole are the most potent CYP2C19 inhibitors. This was confirmed after the incubation of the individual PPIs with human primary hepatocytes (in the presence of human serum) and by monitoring their impact on diazepam N-demethylase activity at a low concentration of diazepam (2 μM). Data described herein are consistent with reports that PPIs are mostly weak inhibitors of cytochromes P450 in vivo. However, two members of the PPI class (esomeprazole and omeprazole) are more likely to serve as clinically relevant inhibitors of CYP2C19.
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Affiliation(s)
- Tatyana Zvyaga
- Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
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Kodaira C, Uchida S, Yamade M, Nishino M, Ikuma M, Namiki N, Sugimoto M, Watanabe H, Hishida A, Furuta T. Influence of different proton pump inhibitors on activity of cytochrome P450 assessed by [(13)C]-aminopyrine breath test. J Clin Pharmacol 2012; 52:432-439. [PMID: 21415279 DOI: 10.1177/0091270010397728] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Aminopyrine is metabolized by cytochrome P450 (CYP) in the liver. The investigators evaluated influences of different PPIs on CYP activity as assessed by the [(13)C]-aminopyrine breath test ([(13)C]-ABT). Subjects were 15 healthy volunteers with different CYP2C19 status (5 rapid metabolizers [RMs], 5 intermediate metabolizers [IMs], and 5 poor metabolizers [PMs]). Breath samples were collected before and every 15 to 30 minutes for 3 hours after oral ingestion of [(13)C]-aminopyrine 100 mg on day 8 of each of the following regimens: control; omeprazole 20 mg and 80 mg, lansoprazole 30 mg, and rabeprazole 20 mg. Changes in carbon isotope ratios in carbon dioxide ((13)CO(2)/(12)CO(2)) in breath samples were measured by infrared spectrometry and expressed as delta-over-baseline (DOB) ratios (‰). Mean areas under the curve of DOB from 0 to 3 h (AUC(0-3h) of DOB) were significantly decreased by omeprazole 20 mg and lansoprazole 30 mg but not by rabeprazole 20 mg. Conversely, higher PPI dose (ie, omeprazole 80 mg) seemed to further decrease AUC(0-3h) of DOB in RMs but increased it in PMs. Omeprazole and lansoprazole at the standard doses inhibit CYP activity but rabeprazole does not, whereas high-dose omeprazole seems to induce CYPs.
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Affiliation(s)
- Chise Kodaira
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
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17
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Saari TI, Uusi-Oukari M, Ahonen J, Olkkola KT. Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology. Pharmacol Rev 2011; 63:243-67. [PMID: 21245208 DOI: 10.1124/pr.110.002717] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABA(A)R) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, β2, and γ2 subunit-containing GABA(A)Rs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABA(A)Rs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABA(A)Rs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABA(A)R agonist remimazolam, have recently been published.
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Affiliation(s)
- Teijo I Saari
- Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, P.O. Box 52 (Kiinamyllynkatu 4-8), FI-20520 Turku, Finland.
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Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41:89-295. [PMID: 19514967 DOI: 10.1080/03602530902843483] [Citation(s) in RCA: 541] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.
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Affiliation(s)
- Shu-Feng Zhou
- School of Health Sciences, RMIT University, Bundoora, Victoria, Australia.
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Schöller-Gyüre M, Kakuda TN, De Smedt G, Vanaken H, Bouche MP, Peeters M, Woodfall B, Hoetelmans RMW. A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers. Br J Clin Pharmacol 2008; 66:508-16. [PMID: 18492125 PMCID: PMC2561103 DOI: 10.1111/j.1365-2125.2008.03214.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2007] [Accepted: 04/21/2008] [Indexed: 12/13/2022] Open
Abstract
AIMS Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV. Proton pump inhibitors and H(2)-antagonists are frequently used in the HIV-negative-infected population, and drug-drug interactions have been described with other antiretrovirals. This study evaluated the effect of steady-state omeprazole and ranitidine on the pharmacokinetics of a single dose of etravirine. METHODS In an open-label, randomized, one-way, three-period crossover trial, HIV-negative volunteers randomly received a single dose of 100 mg etravirine alone (treatment A); 11 days of 150 mg ranitidine b.i.d. (treatment B); and 11 days of 40 mg omeprazole q.d. (treatment C). A single dose of 100 mg etravirine was co-administered on day 8 of sessions 2 and 3. Each session was separated by a 14-day wash-out. RESULTS Nineteen volunteers (seven female) participated. When a single dose of etravirine was administered in the presence of steady-state ranitidine, etravirine least squares means ratios (90% confidence interval) for AUC(last) and C(max) were 0.86 (0.76, 0.97) and 0.94 (0.75, 1.17), respectively, compared with administration of etravirine alone. When administered with steady-state omeprazole, these values were 1.41 (1.22, 1.62) and 1.17 (0.96, 1.43), respectively. Co-administration of a single dose of etravirine and ranitidine or omeprazole was generally safe and well tolerated. CONCLUSIONS Ranitidine slightly decreased etravirine exposure, whereas omeprazole increased it by approximately 41%. The increased exposure of etravirine when co-administered with omeprazole is attributed to CYP2C19 inhibition. Considering the favourable safety profile of etravirine, these changes are not clinically relevant. Etravirine can be co-administered with proton pump inhibitors and H(2) antagonists without dose adjustments.
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Sugimoto M, Furuta T, Nakamura A, Shirai N, Ikuma M, Misaka S, Uchida S, Watanabe H, Ohashi K, Ishizaki T, Hishida A. Maintenance time of sedative effects after an intravenous infusion of diazepam: a guide for endoscopy using diazepam. World J Gastroenterol 2008; 14:5197-5203. [PMID: 18777597 PMCID: PMC2744010 DOI: 10.3748/wjg.14.5197] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2008] [Revised: 06/30/2008] [Accepted: 07/07/2008] [Indexed: 02/06/2023] Open
Abstract
AIM To examine whether the sedative effects assessed by psychomotor tests would depend on the cytochrome P450 (CYP) 2C19 genotypes after an infusion regimen of diazepam commonly used for gastrointestinal endoscopy in Japan. METHODS Fifteen healthy Japanese volunteers consisting of three different CYP2C19 genotype groups underwent a critical flicker fusion test, an eye movement analysis and a postural sway test as a test for physical sedative effects, and a visual analog scale (VAS) symptom assessment method as a test for mental sedative effects during the 336 h period after the intravenous infusion of diazepam (5 mg). RESULTS The physical sedative effects assessed by the critical flicker test continued for 1 h (t values of 5 min, 30 min and 60 min later: 4.35, 5.00 and 3.19, respectively) and those by the moving radial area of a postural sway test continued for 3 h (t values of 5 h, 30 h, 60 min and 3 h later: -4.05, -3.42, -2.17 and -2.58, respectively), which changed significantly compared with the baseline level before infusion (P<0.05). On the other hand, the mental sedative effects by the VAS method improved within 1 h. The CYP2C19 genotype-dependent differences in the postinfusion sedative effects were not observed in any of the four psychomotor function tests. CONCLUSION With the psychomotor tests, the objective sedative effects of diazepam continued for 1 h to 3 h irrespective of CYP2C19 genotype status and the subjective sedative symptoms improved within 1 h. Up to 3 h of clinical care appears to be required after the infusion of diazepam, although patients feel subjectively improved.
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21
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Tomlinson B, Hu M, Lee VWY. In vivoassessment of herb–drug interactions: Possible utility of a pharmacogenetic approach? Mol Nutr Food Res 2008; 52:799-809. [DOI: 10.1002/mnfr.200700454] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Saari TI, Laine K, Bertilsson L, Neuvonen PJ, Olkkola KT. Voriconazole and fluconazole increase the exposure to oral diazepam. Eur J Clin Pharmacol 2007; 63:941-9. [PMID: 17676319 DOI: 10.1007/s00228-007-0350-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2007] [Accepted: 07/04/2007] [Indexed: 10/23/2022]
Abstract
OBJECTIVE We assessed the effect of voriconazole and fluconazole on the pharmacokinetics and pharmacodynamics of diazepam. METHODS Twelve healthy volunteers took 5 mg of oral diazepam in a randomised order on three study sessions: without pretreatment, after oral voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after oral fluconazole 400 mg on the first day and 200 mg on the second day. Plasma concentrations of diazepam and N-desmethyldiazepam were determined for up to 48 h. Pharmacodynamic variables were measured for 12 h. RESULTS In the voriconazole phase, the area under the plasma concentration time curve (AUC 0-infinity) of diazepam was increased (geometric mean ratio) 2.2-fold (p < 0.05; 90% confidence interval [CI] 1.56 to 2.82). This was associated with the prolongation of the mean elimination half-life (t(1/2)) from 31 h to 61 h (p < 0.01) after voriconazole. In the fluconazole phase, the AUC 0-infinity of diazepam was increased 2.5-fold (p < 0.01; 90% CI 1.94 to 3.40), and the t(1/2) was prolonged from 31 h to 73 h (p < 0.001). The peak plasma concentration of diazepam was practically unchanged by voriconazole and fluconazole. The pharmacodynamics of diazepam were changed only modestly. CONCLUSION Both voriconazole and fluconazole considerably increase the exposure to diazepam. Recurrent administration of diazepam increases the risk of clinically significant interactions during voriconazole or fluconazole treatment, because the elimination of diazepam is impaired significantly.
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Affiliation(s)
- Teijo I Saari
- Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, 20520, Turku, Finland.
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Furuta T, Sugimoto M, Kodaira C, Nishino M, Yamade M, Shirai N, Ikuma M, Hishida A, Ishizaki T. Personalized medicine for eradication of Helicobacter pylori. Per Med 2007; 4:321-328. [PMID: 29788670 DOI: 10.2217/17410541.4.3.321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Regimens for eradication of Helicobacter pylori consist of a proton-pump inhibitor (PPI) and one or two antimicrobial agents, such as amoxicillin, clarithromycin or metronidazole. As the pharmacokinetics and pharmacodynamics of PPIs are affected by polymorphism of CYP2C19, doses and dosing schemes of a PPI should be optimized based on genotype status of each patient in order to yield higher eradication rates. PPIs affect the pharmacokinetics of other substrates of CYP2C19, such as warfarin and diazepam. Acid inhibition induced by a PPI also affects the pharmacokinetics of some drugs, such as itraconazole. Clarithromycin, one of the most frequently used antimicrobial agents in eradication of H. pylori, inhibits activity of CYP3A4, meaning that the pharmacokinetics of substrates of CYP3A4 are affected by clarithromycin. Therefore, clinicians must pay attention to the other drugs dosed to each of their patients. Therefore, the eradication regimen for H. pylori infection should be designed with the CYP2C19 genotype status, bacterial susceptibility to antimicrobial agents, and other drugs being taken by each patient having been taken into consideration.
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Affiliation(s)
- Takahisa Furuta
- Hamamatsu University School of Medicine, Center for Clinical Research, Hamamatsu, 1-20-1, Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.
| | - Mitushige Sugimoto
- Hamamatsu University School, of Medicine, First Department of Medicine, Hamamatsu, Japan
| | - Chise Kodaira
- Hamamatsu University School, of Medicine, First Department of Medicine, Hamamatsu, Japan
| | - Masafumi Nishino
- Hamamatsu University School, of Medicine, First Department of Medicine, Hamamatsu, Japan
| | - Mihoko Yamade
- Hamamatsu University School, of Medicine, First Department of Medicine, Hamamatsu, Japan
| | - Naohito Shirai
- Enshu General Hospital, Department of Gastroenterology, Hamamatsu, Japan
| | - Mutsuhiro Ikuma
- Hamamatsu University School, of Medicine, First Department of Medicine, Hamamatsu, Japan
| | - Akira Hishida
- Hamamatsu University School, of Medicine, First Department of Medicine, Hamamatsu, Japan
| | - Takashi Ishizaki
- Hamamatsu University School of Medicine, Department of Clinical Pharmacology and Therapeutics, Hamamatsu, Japan
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Shimatani T, Inoue M, Kuroiwa T, Moriwaki M, Xu J, Ikawa K, Morikawa N, Tazuma S. Which has superior acid-suppressive effect, 10 mg omeprazole once daily or 20 mg famotidine twice daily? Effects of single or repeated administration in Japanese Helicobacter pylori-negative CYP2C19 extensive metabolizers. Dig Dis Sci 2007; 52:390-5. [PMID: 17211705 DOI: 10.1007/s10620-006-9490-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2006] [Accepted: 06/14/2006] [Indexed: 12/29/2022]
Abstract
Low-dose omeprazole is superior to full-dose famotidine in maintenance therapy for gastroesophageal reflux disease, whereas "on-demand" famotidine is more effective for relief of episodes of heartburn. To explain this apparent discrepancy, intragastric pH was measured for 24-hr seven times in eight Japanese Helicobacter pylori-negative cytochrome P450 2C19 extensive metabolizers; on Days 1, 8, and 15 of repeated administration of 10 mg of omeprazole once daily and of 20 mg of famotidine twice daily and before medication. During repeated administration of omeprazole, mean intragastric pH and % time that intragastric pH > 4.0 were significantly higher and became greater. With famotidine, although these parameters were significantly higher, the degrees became smaller. Consequently, acid-suppressive effect was in the order; omeprazole < famotidine on Day 1, omeprazole approximately famotidine on Day 8, and omeprazole >famotidine on Day 15. This discrepancy possibly results from the "potentiation" of acid-suppressive effect of omeprazole and the "tolerance" phenomenon in respect to famotidine.
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Affiliation(s)
- Tomohiko Shimatani
- Department of General Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Hiroshima, Japan.
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Abstract
Proton pump inhibitors are used extensively for the treatment of gastric acid-related disorders because they produce a greater degree and longer duration of gastric acid suppression and, thus, better healing rates, than histamine H(2) receptor antagonists. The need for long-term treatment of these disorders raises the potential for clinically significant drug interactions in patients receiving proton pump inhibitors and other medications. Therefore, it is important to understand the mechanisms for drug interactions in this setting. Proton pump inhibitors can modify the intragastric release of other drugs from their dosage forms by elevating pH (e.g. reducing the antifungal activity of ketoconazole). Proton pump inhibitors also influence drug absorption and metabolism by interacting with adenosine triphosphate-dependent P-glycoprotein (e.g. inhibiting digoxin efflux) or with the cytochrome P450 (CYP) enzyme system (e.g. decreasing simvastatin metabolism), thereby affecting both intestinal first-pass metabolism and hepatic clearance. Although interactions based on the change of gastric pH are a group-specific effect and thus may occur with all proton pump inhibitors, individual proton pump inhibitors differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole have been studied most extensively. A number of studies have shown that omeprazole carries a considerable potential for drug interactions, since it has a high affinity for CYP2C19 and a somewhat lower affinity for CYP3A4. In contrast, pantoprazole appears to have lower potential for interactions with other medications. Although the interaction profiles of esomeprazole, lansoprazole and rabeprazole have been less extensively investigated, evidence suggests that lansoprazole and rabeprazole seem to have a weaker potential for interactions than omeprazole. Although only a few drug interactions involving proton pump inhibitors have been shown to be of clinical significance, the potential for drug interactions should be taken into account when choosing a therapy for gastric acid-related disorders, especially for elderly patients in whom polypharmacy is common, or in those receiving a concomitant medication with a narrow therapeutic index.
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Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006; 58:521-90. [PMID: 16968950 DOI: 10.1124/pr.58.3.6] [Citation(s) in RCA: 235] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The application of pharmacogenetics holds great promise for individualized therapy. However, it has little clinical reality at present, despite many claims. The main problem is that the evidence base supporting genetic testing before therapy is weak. The pharmacology of the drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathways of elimination. Some have active metabolites or enantiomers with different activities and pathways of elimination. Drug dosing is likely to be influenced only if the aggregate molar activity of all active moieties at the site of action is predictably affected by genotype or phenotype. Variation in drug concentration must be significant enough to provide "signal" over and above normal variation, and there must be a genuine concentration-effect relationship. The therapeutic index of the drug will also influence test utility. After considering all of these factors, the benefits of prospective testing need to be weighed against the costs and against other endpoints of effect. It is not surprising that few drugs satisfy these requirements. Drugs (and enzymes) for which there is a reasonable evidence base supporting genotyping or phenotyping include suxamethonium/mivacurium (butyrylcholinesterase), and azathioprine/6-mercaptopurine (thiopurine methyltransferase). Drugs for which there is a potential case for prospective testing include warfarin (CYP2C9), perhexiline (CYP2D6), and perhaps the proton pump inhibitors (CYP2C19). No other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation. In this review we summarize the current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes.
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Affiliation(s)
- Sharon J Gardiner
- Department of Medicine, Christchurch School of Medicine, Private Bag 4345, Christchurch, New Zealand.
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Hu YM, Mei Q, Xu XH, Hu XP, Hu NZ, Xu JM. Pharmacodynamic and kinetic effect of rabeprazole on serum gastrin level in relation to CYP2C19 polymorphism in Chinese Hans. World J Gastroenterol 2006; 12:4750-3. [PMID: 16937451 PMCID: PMC4087845 DOI: 10.3748/wjg.v12.i29.4750] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the pharmacokinetics and pharmaco-dynamics of rabeprazole and compare serum gastrin concentrations in different CYP2C19 genotype groups.
METHODS: The CYP2C19 genotype status of Chinese Han healthy volunteers was determined by polymerase chain reaction-restriction fragment length polymorphism method. Twenty H pylori-negative healthy subjects voluntary participated in the study. They were divided into the following three groups: homozygous extensive metabolizers (homEM), heterozygous extensive metabolizers (hetEM) and poor metabolizers (PM). After they orally received rabeprazole 20 mg once daily in the morning of d 1 and d 8, blood samples were collected at various time-points until 24 h after administration and intragastric pH values were monitored for 24 h by Digitrapper pH. Serum gastrin concentrations were measured by radioimmunoassay. Serum concentrations of rabeprazole were measured by high performance liquid chromatography.
RESULTS: The mean AUC values for rabeprazole after a single and repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM, or the hetEM and PM groups. No significant differences in intragastric pH medians were observed among the three different genotype groups after a single dose or repeated doses. The ratio of pH medians between d 1 and d 8 ranged from 84% to 108%. The mean gastrin AUC values were also different among the three genotype groups, with a relative ratio of 1.0, 1.2 and 1.5 after a single dose and 1.0, 1.5 and 1.6 after repeated doses in the homEM, hetEM and PM groups, respectively. The gastrin AUC values among the three different genotype groups showed no significant difference either after a single dose or repeated doses. The subject who had lower intragastric acidity showed higher serum gastrin levels and concentrations of rabeprazole.
CONCLUSION: In Chinese Han healthy people, the pharmacokinetics of rabeprazole are dependent on the CYP2C19 genotype status, but acid-inhibitory efficacy of rabeprazole and the gastrin level are not influenced significantly.
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Affiliation(s)
- Yong-Mei Hu
- Department of Gastroenterology, The First Affiliated Hospital, Anhui Medical University, Hefei 230022, Anhui Province, China.
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HORN J. Review article: understanding the pharmacodynamic and pharmacokinetic differences between proton pump inhibitors - focus on pKa and metabolism. ACTA ACUST UNITED AC 2006. [DOI: 10.1111/j.1746-6342.2006.00065.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Shimizu M, Uno T, Yasui-Furukori N, Sugawara K, Tateishi T. Effects of clarithromycin and verapamil on rabeprazole pharmacokinetics between CYP2C19 genotypes. Eur J Clin Pharmacol 2006; 62:597-603. [PMID: 16783561 DOI: 10.1007/s00228-006-0152-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2006] [Accepted: 05/02/2006] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Rabeprazole as a proton pump inhibitor (PPI) is mainly reduced to rabeprazole thioether via a nonenzymatic pathway, with minor CYP2C19 and CYP3A4 involvement. The aim of this study was to compare possible effects of clarithromycin and verapamil as inhibitors of CYP3A4 on the pharmacokinetics of rabeprazole among CYP2C19 genotypes. METHODS A three-way randomized, double-blind, placebo-controlled crossover study was performed. Nineteen volunteers, of whom six were homozygous extensive metabolizers (EMs), eight were heterozygous EMs, and five were poor metabolizers (PMs) for CYP2C19, received three 6-day courses of either daily 800 mg clarithromycin, 240 mg verapamil, or placebo in a randomized fashion, with a single oral dose of 20 mg rabeprazole on day 6 in all cases. Plasma concentrations of rabeprazole and rabeprazole thioether were monitored up to 24 h after the dosing. RESULTS In the control phase, the AUC(0-infinity) values for rabeprazole and rabeprazole thioether were 1,005+/-366 and 412+/-149 ng.h/ml in homozygous EMs, 1,108+/-340 and 491+/-245 ng.h/ml in heterozygous EMs, and 2,697+/-364 and 2,116+/-373 ng.h/ml in PMs, respectively. There were significant differences (p<0.001) in the AUC(0-infinity) of rabeprazole and rabeprazole thioether among three different CYP2C19 genotypes. In the clarithromycin and verapamil phases, no significant differences were found in the pharmacokinetic parameters of rabeprazole compared with those in the control phase irrespective of CYP2C19 genotypes, whereas the AUC(0-infinity) of rabeprazole thioether was significantly increased 2.8-fold and 2.3-fold in homozygous EMs (p<0.01), 2.0-fold and 2.0-fold in heterozygous EMs (p<0.05), and 1.6-fold and 1.9-fold in PMs (p<0.05), respectively. In each genotype group for CYP2C19, there were no statistical differences in the percent increase in those pharmacokinetic parameters between the clarithromycin and verapamil pretreatment phases. CONCLUSION The pharmacokinetic parameters of rabeprazole were not altered by clarithromycin or verapamil irrespective of the CYP2C19 genotypes. However, this result shows that both clarithromycin and verapamil significantly influence the disposition of rabeprazole by inhibiting the oxidation of the thioether, since the AUC(0-infinity) of rabeprazole thioether that has no effect on acid secretion increased. Therefore, the pharmacokinetic interactions between rabeprazole and CYP3A4 or P-glycoprotein inhibitors have limited clinical significance.
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Affiliation(s)
- Mikiko Shimizu
- Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan
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Abstract
The proton pump inhibitors are a very effective drug group for the control of gastric acid secretion, which makes them of great use in the medical practice setting, while at the same time they represent one of the treatment groups widely used in Western European countries. These factors lead to this drug group being prescribed in all age populations, quite often in polymedicated patients and with pluripathology, and on many occasions during prolonged periods of time. All these determinant factors sometimes make the safety profile of proton pump inhibitors disputable. In this respect all of them have been shown to have little adverse events and are safe in long-term treatment. The risk of drug interactions when prescribed in association with other drugs is low and their repercussion in the medical practice setting is quite exceptional as they require few dosage adjustments in patients with severe concomitant diseases and in elderly patients. Finally, their safety is high in pregnant women and in children, although further studies in this population are required to corroborate this evidence.
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Sugimoto M, Furuta T, Shirai N, Nakamura A, Kajimura M, Sugimura H, Hishida A, Ishizaki T. Poor metabolizer genotype status of CYP2C19 is a risk factor for developing gastric cancer in Japanese patients with Helicobacter pylori infection. Aliment Pharmacol Ther 2005; 22:1033-1040. [PMID: 16268979 DOI: 10.1111/j.1365-2036.2005.02678.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Cytochrome P450 2C19 (CYP2C19) polymorphism has been associated with the development of lung, liver or oesophageal cancer by detoxification of carcinogen(s) or activation of procarcinogen(s). AIM To clarify the association between CYP2C19 polymorphisms and gastric cancer development in Japanese. Methods : We determined CYP2C19 genotypes (CYP2C19*1, *2 and *3) in 111 Helicobacter pylori-positive patients with gastric cancer and 315 H. pylori-positive controls without gastric cancer consisting of patients with gastritis only or peptic ulcer. Frequencies of CYP2C19 genotypes and serum pepsinogen I and II levels, a biomarker of gastric atrophy, in the gastric cancers and controls were compared. RESULTS Frequencies of homozygous extensive metabolizers, heterozygous extensive metabolizers and poor metabolizers were 31.5%, 42.3% and 26.2% in the gastric cancers and 38.1%, 47.0% and 14.9% in the controls, respectively (P = 0.046). Poor metabolizers were associated with an increased risk for developing gastric cancer with the age- and sex-adjusted odds ratio (OR) of 1.975 [95% confidence interval (CI): 1.068-3.649], especially for diffuse type (OR: 3.385, CI: 1.187-9.648). There is no significant association between CYP2C19 genotypes and serum pepsinogen I level or pepsinogen I/II ratios, although serum pepsinogen I level in gastric cancers were significantly decreased. CONCLUSIONS In H. pylori-positive Japanese, poor metabolizers of CYP2C19 appear to be at an increased risk for developing gastric cancer, especially diffuse type, and may require an intensive follow-up for scrutinizing possible gastric cancer development.
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Affiliation(s)
- M Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
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Hu YM, Xu JM, Mei Q, Xu XH, Xu SY. Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotype in healthy Chinese subjects. Acta Pharmacol Sin 2005; 26:384-8. [PMID: 15715938 DOI: 10.1111/j.1745-7254.2005.00047.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
AIM To investigate whether the pharmacodynamics and pharmacokinetics of rabeprazole are dependent on CYP2C19 genotype status in healthy Chinese Han subjects. METHODS The CYP2C19 genotype status of healthy Chinese Han volunteers was determined using the polymerase chain reaction-restriction fragment length polymorphism method. Twenty healthy subjects volunteered to participate in the study. There were seven homozygous extensive metabolizers (homEM), six heterozygous extensive metabolizers (hetEM), and seven poor metabolizers (PM). All subjects were Helicobactor pylori-negative, which was determined by sero-logy and 13C-urea breath tests. Rabeprazole (20 mg) was taken orally once daily in the morning for 8 days, and intragastric pH values were monitored for 24 h by Digitrapper pH after day 1 (single dose) and day 8 (repeated dose). Meanwhile, blood samples were collected at various time-points for 24 h after administration. The serum concentrations of rabeprazole were measured using high-performance liquid chromatography. RESULTS The mean area under the curve (AUC) values for rabeprazole differed among the three different genotype groups, with a relative ratio of 1.0, 1.3, and 1.8 after a single dose and 1.0, 1.1, and 1.7 after repeated doses in the homEM, hetEM, and PM groups, respectively. Mean AUC values for rabeprazole after a single dose and after repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM or hetEM and PM groups. No significant differences in intragastric pH median, pH>4 total time, and pH>4 time percentage of 24 h, were observed among the three different genotype groups after a single dose or after repeated doses of rabeprazole. CONCLUSION In healthy Chinese Han subjects, the pharmacokinetics of rabeprazole are dependent on a certain degree on CYP2C19 genotype status; however, the acid-inhibitory efficacy of rabeprazole is not influenced significantly by CYP2C19 genetic polymorphism.
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Affiliation(s)
- Yong-mei Hu
- Anhui Geriatric Institute, Hefei 230022, China.
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Robinson M. Review article: the pharmacodynamics and pharmacokinetics of proton pump inhibitors--overview and clinical implications. Aliment Pharmacol Ther 2004; 20 Suppl 6:1-10. [PMID: 15496213 DOI: 10.1111/j.1365-2036.2004.02160.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
During the past two decades, enormous changes occurred in the management of gastric acid-related diseases. First, the histamine2-receptor antagonists were introduced, offering patients the first single-agent therapy that effectively reduced gastric acid secretion. Proton pump inhibitors became widely available in the early 1990s, and they generally appeared to be superior to the histamine2-receptor antagonists in acid-suppressing activity, symptom control and healing. Most physicians now use proton pump inhibitors as first-line treatment for many patients with acid-peptic disorders, including erosive gastro-oesophageal reflux disease (GERD), nonerosive reflux disease (NERD) and duodenal and gastric ulcers. Although proton pump inhibitors are often thought to be interchangeable, some differences have emerged in their pharmacological properties, which may be reflected in some aspects of clinical efficacy. Such differences include potency, speed of onset and duration of pH 'holding times'. Helicobacter pylori has now been recognized as an important factor in the pathogenesis of acid-peptic disorders. It is clear that H. pylori eradication can dramatically reduce the chronicity of gastric and duodenal ulcers, and accepted therapeutic regimens for H. pylori eradication now include proton pump inhibitors and two or more antibiotics. Although all accepted proton pump inhibitor-based 'triple therapies' are roughly equivalent in efficacy, there is now a shortened regimen available that will potentially enhance compliance and decrease cost. This review examines the relative advantages of proton pump inhibitors vs. histamine2-receptor antagonists in the context of acid suppression and in various gastric acid-related diseases. A brief overview presents the pharmacodynamics and pharmacokinetics of the proton pump inhibitors with particular attention paid to rabeprazole, one of the newer drugs in its class.
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Affiliation(s)
- M Robinson
- Oklahoma Foundation for Digestive Research, University of Oklahoma, Oklahoma City, OK 73104, USA.
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Lim PWY, Goh KL. Review article: efficacy and safety of rabeprazole in treating gastroesophageal reflux disease. J Gastroenterol Hepatol 2004; 19 Suppl 3:S61-8. [PMID: 15324384 DOI: 10.1111/j.1440-1746.2004.03592.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Proton pump inhibitors (PPI) are the mainstay of gastroesophageal reflux disease (GERD) treatment. They have a good efficacy and short- and long-term safety profile. Rabeprazole is a second generation PPI with rapid onset of action that quickly relieves symptoms of GERD. Rabeprazole consistently and profoundly inhibits gastric acid secretion. Its metabolism is less dependent on CYP4502C19 system and therefore is the least affected among all PPIs by CYP4502C19 genetic polymorphism. Recent studies have also indicated that rabeprazole on-demand is cost effective in preventing non-erosive reflux disease (NERD) symptom relapse.
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Affiliation(s)
- P W Y Lim
- Eisai Asia Regional Services Pte Ltd, Singapore.
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Li XQ, Andersson TB, Ahlström M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 2004; 32:821-7. [PMID: 15258107 DOI: 10.1124/dmd.32.8.821] [Citation(s) in RCA: 462] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The human clearance of proton pump inhibitors (PPIs) of the substituted benzimidazole class is conducted primarily by the hepatic cytochrome P450 (P450) system. To compare the potency and specificity of the currently used PPIs (i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) as inhibitors of four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and 3A4), we performed in vitro studies using human liver microsomal preparations and recombinant CYP2C19. Sample analysis was done using selected reaction monitoring liquid chromatography/tandem mass spectometry. With several systems for CYP2C19 activity (two marker reactions, S-mephenytoin 4'-hydroxylation and R-omeprazole 5-hydroxylation, tested in either human liver microsomes or recombinant CYP2C19), the five PPIs showed competitive inhibition of CYP2C19 activity with K(i) of 0.4 to 1.5 microM for lansoprazole, 2 to 6 microM for omeprazole, approximately 8 microM for esomeprazole, 14 to 69 microM for pantoprazole, and 17 to 21 microM for rabeprazole. Pantoprazole was a competitive inhibitor of both CYP2C9-catalyzed diclofenac 4'-hydroxylation and CYP3A4-catalyzed midazolam 1'-hydroxylation (K(i) of 6 and 22 microM, respectively), which were at least 2 times more potent than the other PPIs. All PPIs were poor inhibitors of CYP2D6-mediated bufuralol 1'-hydroxylation with IC(50) > 200 microM. The inhibitory potency of a nonenzymatically formed product of rabeprazole, rabeprazole thioether, was also investigated and showed potent, competitive inhibition with K(i) values of 6 microM for CYP2C9, 2 to 8 microM for CYP2C19, 12 microM for CYP2D6, and 15 microM for CYP3A4. The inhibitory potency of R-omeprazole on the four studied P450 enzymes was also studied and showed higher inhibitory potency than its S-isomer on CYP2C9 and 2C19 activities. Our data suggest that, although the inhibitory profiles of the five studied PPIs were similar, lansoprazole and pantoprazole are the most potent in vitro inhibitors of CYP2C19 and CYP2C9, respectively. Esomeprazole showed less inhibitory potency compared with omeprazole and its R-enantiomer. The inhibitory potency of rabeprazole was relatively lower than the other PPIs, but its thioether analog showed potent inhibition on the P450 enzymes investigated, which may be clinically significant.
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Affiliation(s)
- Xue-Qing Li
- DMPK and Bioanalytical Chemistry, AstraZeneca R and D Mölndal, S-431 83 Mölndal, Sweden
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Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs 2004; 63:2739-54. [PMID: 14664653 DOI: 10.2165/00003495-200363240-00004] [Citation(s) in RCA: 124] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Proton pump inhibitors (PPIs) [omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole] are widely utilised for the treatment of gastro-oesophageal reflux disease, as well as other acid-related disorders. All PPIs suppress gastric acid secretion by blocking the gastric acid pump, H(+)/K(+)-adenosine triphosphatase (ATPase), but the physicochemical properties of these drugs result in variations in the degree of acid suppression, as well as the speed of onset of acid inhibition. Such differences may impact on the clinical performance of PPIs, and this manuscript discusses data that may help clinicians choose between the available PPIs for specific clinical situations and indications. The characteristics of PPIs that have been developed subsequent to omeprazole offer several advantages over this prototype PPI, particularly with respect to the onset of acid suppression and reduced potential for inter-individual pharmacokinetic variation and drug interactions. Newer agents inhibit H(+)/K(+)-ATPase more rapidly than omeprazole and emerging clinical data support potential clinical benefits resulting from this pharmacological property. Although key pharmacokinetic parameters (time to maximum plasma concentration and elimination half-life) do not differ significantly among PPIs, differences in the hepatic metabolism of these drugs can produce inter-patient variability in acid suppression, in the potential for pharmacokinetic drug interactions and, quite possibly, in clinical efficacy. All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, there is minimal risk from the administration of any of them - even to patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the cytochrome P450 (CYP) isoenzymes involved in PPI metabolism (CYP2C19), and this polymorphism has been shown to substantially increase plasma levels of omeprazole, lansoprazole and pantoprazole, but not those of rabeprazole. Hepatic metabolism is also a key determinant of the potential for a given drug to be involved in clinically significant pharmacokinetic drug interactions. Omeprazole has the highest risk for such interactions among PPIs, and rabeprazole and pantoprazole appear to have the lowest risk.Thus, whereas all PPIs have been shown to be generally effective and safely used for the treatment of acid-mediated disorders, there are chemical, pharmacodynamic and pharmacokinetic differences among these drugs that may make certain ones more, or less, suitable for treating different patient subgroups. Of course, the absolute magnitude of risk from any PPI in terms of drug-drug interactions is probably low - excepting interactions occurring as class effects related to acid suppression (e.g. increased digoxin absorption or inability to absorb ketoconazole).
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Affiliation(s)
- Malcolm Robinson
- Department of Medicine, Oklahoma Foundation for Digestive Research, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, USA.
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Abstract
Since their introduction into clinical practice in the 1980s, proton pump inhibitors (PPIs) have proved to be of enormous value in the management of acid peptic disorders. They have become the treatment of choice for most, if not all, acid-related gastrointestinal disorders, including gastroesophageal reflux disease, peptic ulcer, and Zollinger-Ellison syndrome. With approval of an intravenous formulation, the benefits of PPIs are extended to critically ill patients for whom oral drug administration is often unsuitable. Five PPIs are approved for clinical use in the United States. Although they share a common core structure and mechanism of action, it is important to understand the general pharmacology of these agents and how they differ from histamine2-receptor antagonists in order to optimize PPI therapy.
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Affiliation(s)
- Lynda S Welage
- Department of Clinical Sciences, University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, MI 48109, USA.
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Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41:913-58. [PMID: 12222994 DOI: 10.2165/00003088-200241120-00002] [Citation(s) in RCA: 599] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.
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Affiliation(s)
- Zeruesenay Desta
- Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Hospital, Indianapolis 46202, USA
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Abstract
UNLABELLED Rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion. In 8-week studies, among patients with gastro-oesophageal reflux disease (GORD), rabeprazole 20 mg/day or 10mg twice daily was as effective as omeprazole and superior to ranitidine in the healing of GORD. Symptom relief with rabeprazole was superior to that provided by placebo and ranitidine and similar to omeprazole. In long-term trials rabeprazole 10 mg/day was similar to omeprazole 20 mg/day in a 2-year study and superior to placebo in 1-year studies, in both the maintenance of healing and prevention of symptoms in patients with healed GORD. In nonerosive GORD, 4-week studies have shown rabeprazole to be more effective than placebo in relieving heartburn and various other gastrointestinal symptoms. Data among patients with Barrett's oesophagus suggest rabeprazole 20 mg/day may be more effective than placebo in maintaining healing of associated oesophagitis after 1 year of treatment. One-week triple Helicobacter pylori eradication therapy with rabeprazole plus clarithromycin and amoxicillin achieved eradication rates of > or =85%. Rabeprazole is as effective as omeprazole and lansoprazole when included as part of a triple-therapy regimen for the eradication of H. pylori. Eradication rates of >90% were achieved when rabeprazole 20 to 40 mg/day was included as part of a quadruple eradication regimen. As monotherapy for peptic ulcer healing and symptom relief, 4- to 8-week studies have shown rabeprazole 10 to 40 mg/day to be superior to placebo and ranitidine and have similar efficacy to omeprazole. Preliminary 1-year data among 16 patients with Zollinger-Ellison syndrome suggest rabeprazole 60 to 120 mg/day can resolve and prevent the recurrence of symptoms and endoscopic lesions associated with this condition. In clinical trials of up to 2 years' duration the tolerability of rabeprazole is similar to that of placebo, ranitidine and omeprazole. Common adverse events assigned to rabeprazole have been diarrhoea, headache, rhinitis, nausea, pharyngitis and abdominal pain. Histological changes and increases in serum gastrin levels were unremarkable and typical of proton pump inhibitors. No dosage adjustment is necessary in renal and mild to moderate hepatic impairment. CONCLUSION Rabeprazole is a well tolerated proton pump inhibitor. It has proven efficacy in healing, symptom relief and prevention of relapse of peptic ulcers and GORD and can form part of effective H. pylori eradication regimens. It is an important alternative to H(2) antagonists and an additional treatment option to other proton pump inhibitors in the management of acid-related disorders.
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Affiliation(s)
- C I Carswell
- Adis International Limited, Auckland, New Zealand.
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Shirai N, Furuta T, Moriyama Y, Okochi H, Kobayashi K, Takashima M, Xiao F, Kosuge K, Nakagawa K, Hanai H, Chiba K, Ohashi K, Ishizaki T. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Aliment Pharmacol Ther 2001; 15:1929-37. [PMID: 11736724 DOI: 10.1046/j.1365-2036.2001.01108.x] [Citation(s) in RCA: 166] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non-enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual's CYP2C19 status. AIM To investigate the acid inhibitory effects and plasma levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes. METHODS Fifteen healthy volunteers took a daily dose of 20 mg of omeprazole or rabeprazole for 8 days. On post-dose days 1 and 8, 24-h profiles of intragastric pH were recorded and plasma concentrations of omeprazole, rabeprazole and their metabolites were determined. RESULTS After single and repeated doses of omeprazole, the intragastric pH values and plasma concentrations of omeprazole and its metabolites were significantly dependent on the CYP2C19 genotype. Significant differences in the same kinetic and dynamic parameters were also observed after single doses of rabeprazole. Although the plasma levels of rabeprazole differed among the different CYP2C19 genotype groups after repeated doses, no significant differences in intragastric pH values were observed. CONCLUSIONS The acid inhibitory effects of omeprazole and rabeprazole are significantly dependent on the CYP2C19 genotype status, as well as on their intrinsic pharmacokinetic and pharmacodynamic characteristics and dosing schemes.
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Affiliation(s)
- N Shirai
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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41
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Muchoh SN, Ogutu BR, Newton CR, Kokwar GO. High-performance liquid chromatographic determination of diazepam in plasma of children with severe malaria. JOURNAL OF CHROMATOGRAPHY. B, BIOMEDICAL SCIENCES AND APPLICATIONS 2001; 761:255-9. [PMID: 11587356 DOI: 10.1016/s0378-4347(01)00284-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
A sensitive, selective and reproducible reversed-phase HPLC method with ultraviolet detection was developed for the quantification of diazepam in small plasma samples from children with severe malaria. The method involves plasma deproteinization with acetonitrile, followed by liquid-liquid extraction with ethyl acetate-n-hexane. Diazepam was eluted at ambient temperatures from a reversed-phase C18 column with an acidic (pH 3.5) aqueous mobile phase (10 mM KH2PO4-acetonitrile, 69:31, v/v). Calibration curves in spiked plasma were linear from 10 to 200 ng (r2 > or = 0.99). The limit of detection was 5.0 ng/ml, and relative recoveries at 25 and 180 ng were >87%. Intra- and inter-assay relative standard deviations were <15%. There was no interference from drugs commonly administered to children with severe malaria (phenobarbitone, phenytoin, chloroquine, quinine, sulfadoxine, pyrimethamine, halofantrine, cycloguanil, chlorcycloguanil, acetaminophen and salicylate). This method has been used for monitoring plasma diazepam concentrations in children with seizures associated with severe malaria.
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Affiliation(s)
- S N Muchoh
- Kenya Medical Research Institute/Wellcome Trust Collaborative Research Programme, Nairobi.
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42
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Gerson LB, Triadafilopoulos G. Proton pump inhibitors and their drug interactions: an evidence-based approach. Eur J Gastroenterol Hepatol 2001; 13:611-6. [PMID: 11396546 DOI: 10.1097/00042737-200105000-00025] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The proton pump inhibitors (PPIs) are the most effective antisecretory agents used to treat acid-related disorders. As such, they are frequently prescribed for patients who are concurrently using other medications. PPIs may interact with other drugs through numerous mechanisms. The most important include competitive inhibition of hepatic cytochrome P (CYP) 450 enzymes involved in drug metabolism, and alteration of the absorption of other drugs via changes in gastric pH levels. Poor metabolizers, who lack CYP2C19, may be particularly predisposed to drug interactions. Although the potential for drug interactions is high, few clinically significant interactions have been reported for the PPIs. Nevertheless, caution is indicated when certain drugs are co-prescribed with these agents. The incidence of clinically significant drug interactions increases proportionately with the number of drugs taken and with the age of the patient. The drug interaction with the greatest clinical importance is the reduction in benzodiazepine clearance by omeprazole.
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Affiliation(s)
- L B Gerson
- Division of Gastroenterology, Stanford University School of Medicine, CA, USA
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43
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Furuta S, Kamada E, Suzuki T, Sugimoto T, Kawabata Y, Shinozaki Y, Sano H. Inhibition of drug metabolism in human liver microsomes by nizatidine, cimetidine and omeprazole. Xenobiotica 2001; 31:1-10. [PMID: 11334262 DOI: 10.1080/00498250110035615] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
1. The inhibitory effects of cimetidine, nizatidine and omeprazole on the metabolic activity of CYP2C9, 2C19, 2D6 and 3A were investigated in human liver microsomes. Both cimetidine and omeprazole inhibited each of the CYP subfamily enzymes; in particular, omeprazole extensively inhibited the hydroxylation of S-mephenytoin (CYP2C19, Ki = 7.1 microM). Nizatidine exhibited no inhibition of any of the CYP isoforms examined. 2. Cimetidine inhibited the hydroxylation of tolbutamide but not of diclofenac, whereas omeprazole inhibited the hydroxylation of diclofenac but not that of tolbutamide. The ability to inhibit CYP2C9 varied with incubation time, as measured by the metabolic rate constant for the substrates. Therefore, suitable substrates and incubation times must be selected in inhibition studies examining metabolic clearance and the mechanism of inhibition of these drugs. 3. Nizatidine did not inhibit the metabolism of cisapride, glibenclamide, benidipine and simvastatin. Omeprazole inhibited the metabolism of cisapride (Ki = 0.4 microM), glibenclamide (11.7 microM) and benidipine (6.5 microM), whereas cimetidine inhibited the metabolism of glibenclamide (11.6 microM). To avoid drug-drug interactions, care needs to be taken to select suitable medicines for co-administration with anti-ulcer drugs.
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Affiliation(s)
- S Furuta
- Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, Ohsato-gun, Saitama, Japan.
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44
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Humphries TJ. Treatment strategies for gastroesophageal reflux disease. Clin Ther 2000; 22:1590-1. [PMID: 11192149 DOI: 10.1016/s0149-2918(00)83056-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Abstract
OBJECTIVE This paper presents a synopsis of the pathophysiology of gastroesophageal reflux disease (GERD) and the efficacy, safety, and cost of the agents commonly used in its treatment. BACKGROUND Symptomatic relief of GERD can be obtained with lifestyle changes (avoidance of factors that may exacerbate symptoms, such as overeating and use of alcohol and tobacco) and use of over-the-counter medications such as antacids or histamine-2 (H2)-receptor antagonists. When these measures are unsuccessful, treatment with prescription-strength medications is required to prevent complications, such as Barrett's esophagus or esophageal adenocarcinoma. METHODS Current guidelines for the management of GERD were identified through a MEDLINE search of the English-language literature from January 1995 through December 1999 and a search of the bibliographies of identified articles. CONCLUSION Patients who do not respond to initial therapy should be managed with prescription-strength H2-receptor antagonists. Endoscopy should be considered for patients with atypical or refractory symptoms. Patients with a confirmed diagnosis of refractory GERD, severe esophagitis, Barrett's esophagus, or peptic stricture should be treated with and maintained on a proton-pump inhibitor.
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Affiliation(s)
- E M Vivian
- Department of Pharmacy Practice and Administration, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Pennsylvania 19104-4495, USA
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46
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Brockmöller J, Kirchheiner J, Meisel C, Roots I. Pharmacogenetic diagnostics of cytochrome P450 polymorphisms in clinical drug development and in drug treatment. Pharmacogenomics 2000; 1:125-51. [PMID: 11256586 DOI: 10.1517/14622416.1.2.125] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
The current use and future perspectives of molecular genetic characterisation of cytochrome P450 enzymes (CYP) for drug development and drug treatment are summarised. CYP genes are highly polymorphic and the enzymes play a key role in the elimination of the majority of drugs from the human body. Frequent variants of some enzymes, CYP2A6, 2C9, 2C19 and 2D6, should be analysed in participants of clinical trials whenever these enzymes may play a role. It is suggested that a CYP genotype certificate is handed out to the volunteers or patients to avoid replicate analyses, and to allow that this information is available for future research and also for treatment with eventually needed drugs. Guidelines on what CYP alleles have to be analysed in drug development, as well as on analytical validation and CYP genotype data handling will be required. Treatment with several drugs may be improved by prior genotyping. The concepts and problems of CYP genotype-based clinical dose recommendations are presented and illustrated for selected drugs. The requirement for prospective trials on the medical and economic benefits of routine CYP genotyping is emphasised. Specific operationally defined recommendations dependent on genotype are a prerequisite for such studies and this review presents tentative CYP genotype-based dose recommendations systematically calculated from published data. Because of the multiplicity of factors involved, these doses will not be the optimal doses for each given individual, but should be more adequate than doses generally recommended for an average total population. Those CYP alleles and polymorphically metabolised drugs which are currently most interesting in drug development and drug treatment are reviewed, and more complete information is available from websites cited in this article.
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Affiliation(s)
- J Brockmöller
- Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University, Berlin, Germany.
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Abstract
As Helicobacter pylori plays an important role in the aetiopathogenesis of peptic ulcer, therapeutic strategies aimed at maintaining long term remission have shifted from the control of intragastric pH to targeting H. pylori. According to recent international guidelines the clinical goals--rapid ulcer healing and prevention of relapse--can be best accomplished by combination therapy consisting of an antisecretory drug (proton pump inhibitor or ranitidine) and 2 antimicrobial agents (preferable amoxicillin, clarithromycin or metronidazole). When applying such multidrug regimens, possible synergy between the agents suggests that pharmacokinetic considerations might help to improve H. pylori eradication rates, which should be above 85 to 90% on an intention-to-treat basis. The present review summarises the pharmacokinetic properties and interaction potential of all drugs presently used in the various H. pylori eradication regimens, with emphasis on particular patient populations such as the elderly and those with renal impairment. The drugs considered are omeprazole, lansoprazole, pantoprazole, rabeprazole, ranitidine and ranitidine bismutrex, bismuth salts, amoxicillin, clarithromycin, azithromycin, roxithromycin, metronidazole, tinidazole and tetracycline. When addressing the clinically important questions of the efficacy, safety and costs of the recommended regimens, the impact of drug disposition on H. pylori eradication should not be neglected.
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Affiliation(s)
- U Klotz
- Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
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48
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Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION (WASHINGTON, D.C. : 1996) 2000; 40:52-62; quiz 121-3. [PMID: 10665250 DOI: 10.1016/s1086-5802(16)31036-1] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To review the comparative efficacy and safety of the proton pump inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole, and rabeprazole--in the management of acid-related diseases. DATA SOURCES English-language journal articles retrieved from a MEDLINE search from 1990 to the present using these index terms: proton pump inhibitors, omeprazole, lansoprazole, pantoprazole, rebeprazole, and each of the acid-related diseases. STUDY SELECTION Clinical trials and pertinent review articles that discussed the pharmacology, pharmacokinetics, efficacy, and safety of PPIs in the management of acid-related disease. DATA EXTRACTION By the authors. DATA SYNTHESIS PPIs are substituted benzimidazoles that inhibit gastric acid secretion by covalently binding to the proton pump (H+/K+ ATPase). All undergo extensive hepatic metabolism and conjugation. The four agents differ in their metabolism by and effects on specific hepatic enzymes and thus in their ability to interact with other medications. PPIs are important agents used for eradicating Helicobacter pylori, in treating peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison syndrome, and upper gastrointestinal bleeding, and for preventing acid aspiration. Short-term side effects of the four agents are similar. The long-term safety of pantoprazole and rabeprazole appears similar to that of omeprazole and lansoprazole. Pantoprazole, which is in the final stages of approval for marketing in the United States, will be available in both an oral and injectable formulation. CONCLUSION Based on superior efficacy profiles, PPIs are the drugs of choice in managing patients with peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. The decision to select one PPI versus another is most likely to be based on the agents' acquisition costs, formulations, FDA-labeled indications, and overall safety profiles. Intravenous or parenteral pantoprazole may become the preferred antisecretory agent for patients unable to take oral medications (e.g., critically ill patients and those with Zollinger-Ellison syndrome).
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Affiliation(s)
- L S Welage
- College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
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Abstract
Rabeprazole is a new member of a class of substituted benzimidazole drugs known as proton pump inhibitors. Comparative trials have demonstrated that it is at least as effective as omeprazole for the treatment of gastrooesophageal reflux disease (GERD), duodenal ulcers, or gastric ulcers. It is significantly more effective than histamine2-receptor antagonists for acid suppression, GERD healing and pain relief, and duodenal ulcer healing and pain relief. Adverse events reported during clinical trials provide an important indication of a medication's tolerability. We demonstrate that rabeprazole has a favourable adverse events profile. It is well tolerated in placebo-controlled studies and comparative trials with omeprazole and H2-receptor antagonists. Moreover, no dose adjustments are required for special populations, such as the elderly or patients with renal or mild-to-moderate hepatic disease. Adverse events data from clinical trials support the use of rabeprazole as a treatment for acid-related diseases.
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Affiliation(s)
- B Thjodleifsson
- Department of Gastroenterology, National Hospital, Reykjavik, Iceland.
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50
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Abstract
Rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion and has a more rapid onset of action than omeprazole. Duodenal ulcers healed faster after treatment with rabeprazole 20 or 40 mg/day than placebo or ranitidine 150 mg 4 times daily and at a generally similar rate to omeprazole 20 mg/day in patients with duodenal ulcers; rabeprazole was similar or superior to these agents in relieving symptoms. Rabeprazole 20 and 40 mg/day healed gastric ulcers faster than placebo, and rabeprazole 20 mg/day healed ulcers at a similar healing rate, to omeprazole 20 mg/day in well controlled 6-week studies. Gastric ulcer symptom relief with rabeprazole was similar or superior to that provided by omeprazole or placebo. In 8-week studies in patients with gastro-oesophageal reflux disease (GERD), rabeprazole 10, 20 and 40 mg/day were more effective than placebo, rabeprazole 20 mg/day was more effective than ranitidine 150 mg twice daily, and rabeprazole 20 mg/day was similar in efficacy to omeprazole 20 mg/day. Symptom relief with rabeprazole in 8-week trials in patients with GERD was superior to that provided by placebo, and similar to ranitidine or omeprazole. Rabeprazole was similar to omeprazole and superior to placebo in both maintenance of healing and prevention of symptoms in patients with healed GERD in 1-year studies. One-week triple therapy with rabeprazole 20 mg twice daily plus 2 antibacterial agents achieved > or = 90% Helicobacter pylori eradication, but, as would be expected, a regimen of rabeprazole 20 mg twice daily plus 1 antibacterial agent was less successful. The drug was as effective as omeprazole and lansoprazole as part of triple therapy for H. pylori eradication. Rabeprazole successfully reduced acid output to target levels and prevented further pathological changes in 10 patients with Zollinger-Ellison syndrome. Usual dosages of rabeprazole are 20 mg/day for 4 weeks to treat duodenal ulcers, 6 weeks for gastric ulcers and 8 weeks for GERD, although some patients with duodenal ulcer may respond to a 10 mg/day dosage. For long term maintenance of GERD healing, 10 or 20 mg daily doses are adequate. Patients with hypersecretory states may need individualised dosages starting at 60 mg/day. The drug was well tolerated in clinical trials, with headache, rash, infection, diarrhoea and flu syndrome as the most common adverse events. In conclusion, rabeprazole appears to be a well tolerated proton pump inhibitor with a rapid onset of action and a low potential for drug interactions. The drug may be used to achieve healing and the relief of symptoms of duodenal ulcer, gastric ulcer and GERD, maintain GERD healing, and can form part of effective regimens to eradicate H. pylori.
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Affiliation(s)
- H D Langtry
- Adis International Limited, Auckland, New Zealand.
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