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

AIMS

Cytochrome P450 2C19 metabolizes many important drugs. In 2006, a variant allele (CYP2C1917) associated with increased activity was discovered, but its likely clinical significance is controversial. Investigators disagree about the phenotype to be assigned to the two CYP2C1917 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

CYP2C1917 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 CYP2C191/17 heterozygotes and wild-type homozygotes. Even for CYP2C1917 homozygotes, the absolute effect was modest compared with the effect of previously identified loss-of-function alleles. In Helicobacter pylori eradication CYP2C192 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 CYP2C1917 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 CYP2C1917 homozygotes as extensive metabolizers rather than ultrarapid metabolizers is adequate. CYP2C1917 genotyping is unlikely to have clinical utility except for drugs with very narrow therapeutic indices.