Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers

AIMS

To investigate the influence of the CYP2C19*17 allele on the pharmacokinetics of omeprazole, a commonly used CYP2C19 probe drug, in healthy volunteers.

METHODS

In a single-dose pharmacokinetic study, 17 healthy White volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1 received an oral dose of 40 mg of omeprazole. Plasma was sampled for up to 10 h postdose, followed by quantification of omeprazole, 5-hydroxy omeprazole and omeprazole sulphone by high-performance liquid chromatography.

RESULTS

The mean omeprazole AUC_∞ of 1973 h nmol l^?1 in CYP2C19*17/*17 subjects was 2.1-fold lower 95% confidence interval (CI) 1.1, 3.3] than in CYP2C19*1/*1 subjects (4151 h nmol l^?1, P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC_∞ of 1083 h nmol l^?1, 3.1-fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l^?1, P = 0.03). A pronounced correlation (r² = 0.95, P < 0.0001) was seen in the intraindividual omeprazole AUC_∞ and omeprazole sulphone AUC_∞ values.

CONCLUSIONS

The pharmacokinetics of omeprazole and omeprazole sulphone differ significantly between homozygous CYP2C19*17 and CYP2C19*1 subjects. For clinically important drugs that are metabolized predominantly by CYP2C19, the CYP2C19*17 allele might be associated with subtherapeutic drug exposure.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The only existing study of CYP2C19*17-associated alterations in drug pharmacokinetics was retrospective and compared probe drug metabolic ratios.
• The CYP2C19*17 allele had been associated with a two- and fourfold decrease in omeprazole and S/R-mephenytoin metabolic ratios.

WHAT THIS STUDY ADDS

• This study characterized the single-dose pharmacokinetics of omeprazole, along with the 5-hydroxy and sulphone metabolites, in CYP2C19*17/*17 and CYP2C19*1/*1 subjects.
• The observed differences in omeprazole AUC_∞ suggest that the CYP2C19*17 allele is an important explanatory factor behind individual cases of therapeutic failure.