Portal de Periódicos da CAPES

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

2008; Wiley; Volume: 65; Issue: 5 Linguagem: Inglês

10.1111/j.1365-2125.2008.03104.x

1365-2125

R. Michael Baldwin, Staffan Ohlsson, Rasmus S. Pedersen, Jessica Mwinyi, Magnus Ingelman‐Sundberg, Erik Eliasson, Leif Bertilsson,

Antibiotics Pharmacokinetics and Efficacy

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. 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 ( r 2 = 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.