Article

Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism

Division of Clinical Pharmacology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States
Clinical Pharmacokinetics (Impact Factor: 5.05). 02/2002; 41(12):913-58. DOI: 10.2165/00003088-200241120-00002
Source: PubMed

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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    • "This is in line with previous literature reports, where CYP2C19 was identified as one of the most important polymorphic CYP enzymes across different populations . Approximately 3–5% of Caucasians and 15–20% of Asians are CYP2C19 poor metabolizers (PMs) with no remaining CYP2C19 functionality (Desta et al., 2002). The importance of CYP2C19 on clopidogrel treatment effect has been confirmed by numerous clinical studies, which show that patients with decreased CYP2C19 activity, i.e. intermediate metabolizers (IMs) or PMs, have remarkably higher on-treatment platelet reactivity and, thus, an increased risk in experiencing ischemic events following administration of the standard dosing regimen. "
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    ABSTRACT: Clopidogrel (Plavix®), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI-1 and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2). The developed model characterized the in vivo disposition of clopidogrel, its bioactivation into clop-AM in the liver and subsequent platelet aggregation inhibition reasonably well. It further allowed the identification of covariates that significantly impact clopidogrel's dose-concentration-response relationship. In particular, CYP2C19 intermediate and poor metabolizers converted 26.2% and 39.5% less clopidogrel to clop-AM, respectively, compared to extensive metabolizers. In addition, CES1 G143E mutation carriers have a reduced CES1 activity (82.9%) compared to wild-type subjects, which results in a significant increase in clop-AM formation. An increase in BMI was found to significantly decrease clopidogrel's bioactivation, whereas increased age was associated with increased platelet reactivity. Our PK/PD model analysis suggests that, in order to optimize clopidogrel dosing on a patient-by-patient basis, all of these factors have to be considered simultaneously, e.g. by using quantitative clinical pharmacology tools.
    No preview · Article · Nov 2015 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
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    • "D. Yu et al. / Biochemical Pharmacology xxx (2015) xxx–xxx 5 negatively regulating the expression of CYP2C19 in liver cells and elucidated the underlying biological mechanism. Since CYP2C19 is involved in the biotransformation of many clinical drugs and environmental toxicants [1] "
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    ABSTRACT: Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of many drugs. Extensive studies have demonstrated that genetic variants and endogenous and environmental factors play important roles in the expression of CYP2C19. However, the role of microRNAs (miRNAs) in controlling CYP2C19 expression has not been investigated completely. In the present study, we performed in silico analysis to rank putative miRNA/CYP2C19 hybrids with regards to the predicted stabilities of their duplexes and then we applied a series of biochemical and molecular assays to elucidate the underlying functional mechanisms for the regulation of CYP2C19 by miRNAs. In silico analysis indicated that hsa-miR-23a-3p and hsa-miR-29a-3p target the coding region of CYP2C19 with hybrid stabilities of -27.5kcal/mol and -23.3kcal/mol, respectively. RNA electrophoresis mobility shift assays showed that both hsa-miR-23a-3p and hsa-miR-29a-3p miRNAs were able to bind directly to their cognate targets in the CYP2C19 transcript. Further, a significant inverse correlation was found between chemically-induced up-regulation of hsa-miR-29a-3p and CYP2C19 expression in HepaRG cells. In addition, inverse correlations were also observed in human liver tissue samples between the level of CYP2C19 mRNA expression and both hsa-miR-23a-3p and hsa-miR-29a-3p levels. All these results demonstrated the suppressing role of hsa-miR-29a-3p on CYP2C19 expression. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Biochemical pharmacology
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    • "insufficient for identifying all poor metabolizers (PMs) of CYP2C19 in the general population. Conventional in vivo CYP2C19 phenotype tests (e.g., S-mephenytoin 4-hydroxylation or omeprazole 5-hydroxylation) are attractive tools because they can capture changes in CYP2C19 activity caused by both genetic and nongenetic factors (Desta et al., 2002). However, their routine clinical use has been limited because these procedures are time and resource intensive and invasive. "
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    ABSTRACT: The phenotype pantoprazole-<13>C breath test (Ptz-BT) was used to evaluate the extent of phenoconversion of cytochrome P450 2C19 (CYP2C19) caused by commonly prescribed proton pump inhibitors (PPI) omeprazole and esomprazole. A single center open label three visit study with 26 healthy volunteers and 8 stable cardiovascular patients was conducted from March 2014 to December 2014 in an institutional review board (IRB) approved study. The Ptz-BT was administered to each volunteer/patient on their first two visits two weeks apart to ascertain the baseline CYP2C19 enzyme activity using the biomarker 13CO2 in breath. After their second visit the volunteers/patients took either omeprazole or esomeprazole for 28 days, and the Ptz-BT was administered on their third visit to evaluate changes in CYP2C19 phenotype. Phenotype conversion resulted in 25 of 26 (96%) non-poor metabolizer (PM) volunteers as measured by the Ptz-BT both before and after PPI therapy. In our study population the incidence of PM status by phenotype following administration of omeprazole/esomeprazole (known inhibitors of CYP2C19) was 10-fold higher than those who are genetically PMs in the general population which could have critical clinical implications for personalizing medications primarily metabolized by CYP2C19 such as clopidogrel, PPI, cyclophosphamide, thalidomide, citalopram, clonazepam, diazepam, phenytoin etc. The Ptz-BT can rapidly (30 min) evaluate CYP2C19 phenotype and, more importantly, can identify patients with phenoconversion in CYP2C19 enzyme activity caused by non-genetic factors such as concomitant drugs. The American Society for Pharmacology and Experimental Therapeutics.
    Full-text · Article · Jul 2015 · Journal of Pharmacology and Experimental Therapeutics
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