Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CYP2C19 polymorphisms may have clinical consequences in relation to drugs extensively metabolized by the enzyme. • Recently a new variant CYP2C19*17 was discovered. • Unlike other commonly studied variant alleles, notably CYP2C19*2 and CYP2C19*3, which are defective, CYP2C19*17 is associated with enhanced enzyme activity and three CYP2C19 phenotypes have been suggested: ultrarapid metabolizers (UM), extensive metabolizers (EM) and poor metabolizers (PM). • There appears to be interethnic variability in the prevalence of the CYP2C19*17 allele. WHAT THIS STUDY ADDS • We provide the first critical quantitative review of this rapidly developing area of research to serve as a basis for subsequent research and overviews. • We summarize data on population prevalence and functional effects of CYP2C19*17. • We argue on the basis of current evidence that potentially significant clinical effects are unlikely except for drugs with very narrow therapeutic windows. Of studied substrates, only clopidogrel may fall into this category. Even then, only homozygotes of the variant allele are likely to be at significantly increased risk. • The assignment of CYP2C19*17 homozygotes as EM, rather than UM, is adequate as the metabolic ratios of all probe drugs studied so far overlap completely the range of values seen in wild‐type homozygotes. • The implications of CYP2C19*17 on the clinical effects of tamoxifen require further study. AIMS Cytochrome P450 2C19 metabolizes many important drugs. In 2006, a variant allele (CYP2C19*17) associated with increased activity was discovered, but its likely clinical significance is controversial. Investigators disagree about the phenotype to be assigned to the two CYP2C19*17 genotypes. The aim of this study was to provide a critical summary, helpful to prescribers. METHODS We searched MEDLINE for papers on the allele from 2006 and then undertook historical searches through the reference lists of papers retrieved. The relevant information was critically assessed and summarized. RESULTS CYP2C19*17 was associated with increased enzymic activity. Substrates studied were omeprazole, pantoprazole, escitalopram, sertraline, voriconazole, tamoxifen and clopidogrel. Most studies used pharmacokinetic variables as outcome measure. For clopidogrel, activated by CYP2C19, pharmacodynamic consequences focused on platelet aggregation. While for most pharmacokinetic parameters of the substrates studied the average value was altered, the range of values showed mostly complete overlap for CYP2C19*1/*17 heterozygotes and wild‐type homozygotes. Even for CYP2C19*17 homozygotes, the absolute effect was modest compared with the effect of previously identified loss‐of‐function alleles. In Helicobacter pylori eradication CYP2C19*2 carriage was associated with an altered eradication rate (odds ratio 4.20, 95% confidence interval 1.23, 16.44) relative to the wild‐type, but CYP2C19*17 homozygosity was not. Prevalence of the variant allele was typically <5% in Asians and about four times higher in White and African populations. CONCLUSIONS Assignment of CYP2C19*17 homozygotes as extensive metabolizers rather than ultrarapid metabolizers is adequate. CYP2C19*17 genotyping is unlikely to have clinical utility except for drugs with very narrow therapeutic indices.