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

Abstract

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(infinity) suggest that the CYP2C19*17 allele is an important explanatory factor behind individual cases of therapeutic failure. 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(infinity) 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(infinity) 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 (r(2) = 0.95, P < 0.0001) was seen in the intraindividual omeprazole AUC(infinity) and omeprazole sulphone AUC(infinity) 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.

Figures

Figure 1

(A) Distribution of area under the concentration–time curve (AUC∞) values for omeprazole, 5-hydroxyomeprazole (5-hydroxy) and omeprazole sulphone (sulphone) in relation to CYP2C19*17/*17 (n = 5) and CYP2C19*1/*1 (n = 11) genotype. (B) Distribution of the ratio of area under the concentration–time curves of omeprazole (OME AUC∞) and 5-hydroxy omeprazole (5-OH AUC∞) in relation to CYP2C19*17/*17 (n = 5) and CYP2C19*1/*1 (n = 11) genotype. Bars represent mean values. Statistical analyses were performed with an unpaired two-tailed heteroscedastic t-test

Figure 2

Correlation of intraindividual omeprazole AUC∞ and metabolite AUC∞ values in CYP2C19*17/*17 (,n = 5) and CYP2C19*1/*1 (•, n = 11) subjects. (A) Relationship between omeprazole AUC∞ and omeprazole sulphone (Sulphone) AUC∞. Linear regression yields r2 = 0.9540 (P < 0.0001). (B) Relationship between omeprazole AUC∞ and 5-hydroxy omeprazole (5-OH) AUC∞. Linear regression yields r2 = 0.5100