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

Abstract

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.

Figure 1

Metabolic ratio of omeprazole and mephenytoin in Swedes and Ethiopians of different genotypes

Figure 2

Metabolic ratio of omeprazole in subjects with different CYP2C19 genotypes

Figure 3

Range of concentrations of escitalopram seen in subjects with different CYP2C19 genotypes. Reprinted by permission from Macmillan Publishers Ltd: [Clin Pharmacol Ther 2008; 83: 322, copyright (2008)

Figure 4

Odds ratio of successful eradication of Helicobacter pylori according to CYP2C19 genotype [24]

Figure 5

Frequency of CYP2C19*17 allele in different populations

Figure 6

Metabolic ratio for omeprazole as a function of CYP2C19 genotype