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

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.

[1]  H. Refsum,et al.  Impact of the Ultrarapid CYP2C19*17 Allele on Serum Concentration of Escitalopram in Psychiatric Patients , 2008, Clinical pharmacology and therapeutics.

[2]  Hua Jiang,et al.  Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide-based regimens in multiple myeloma , 2007, Haematologica.

[3]  S. Penzak,et al.  Does Metronidazole Interact with CYP3A Substrates by Inhibiting Their Metabolism Through This Metabolic Pathway? Or Should Other Mechanisms Be Considered? , 2007, The Annals of pharmacotherapy.

[4]  M. Hayakari,et al.  Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations , 2007, European Journal of Clinical Pharmacology.

[5]  T. Starzynska,et al.  Effect of CYP2C19*17 gene variant on Helicobacter pylori eradication in peptic ulcer patients , 2006, European Journal of Clinical Pharmacology.

[6]  R. Hunt,et al.  The Effect of CYP2C19 Polymorphisms on H. pylori Eradication Rate in Dual and Triple First-Line PPI Therapies: A Meta-analysis , 2006, The American Journal of Gastroenterology.

[7]  U. Klotz.  Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. , 2006, International journal of clinical pharmacology and therapeutics.

[8]  Y. Böttiger.  Use of omeprazole sulfone in a single plasma sample as a probe for CYP3A4 , 2006, European Journal of Clinical Pharmacology.

[9]  Leif Bertilsson,et al.  A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants , 2006, Clinical pharmacology and therapeutics.

[10]  D. Kwiatkowski,et al.  Haplotype block structure of the cytochrome P450 CYP2C gene cluster on chromosome 10 , 2005, Nature Genetics.

[11]  A. Munakata,et al.  Effects of clarithromycin on lansoprazole pharmacokinetics between CYP2C19 genotypes. , 2005, British journal of clinical pharmacology.

[12]  Zeruesenay Desta,et al.  Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis. , 2004, Arthritis and rheumatism.

[13]  U. Klotz,et al.  CYP2C19 polymorphism and proton pump inhibitors. , 2004, Basic & clinical pharmacology & toxicology.

[14]  J Licinio,et al.  Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response , 2004, Molecular Psychiatry.

[15]  L. Bertilsson,et al.  Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. , 2003, British journal of clinical pharmacology.

[16]  Hong-Guang Xie,et al.  Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects , 1999 .

[17]  K. Ohashi,et al.  Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans , 1999, Clinical pharmacology and therapeutics.

[18]  Kyoichi Ohashi,et al.  Effect of Genetic Differences in Omeprazole Metabolism on Cure Rates for Helicobacter pylori Infection and Peptic Ulcer , 1998, Annals of Internal Medicine.

[19]  T. Andersson,et al.  Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. , 1998, British journal of clinical pharmacology.

[20]  L. Bertilsson,et al.  Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects , 1997, Clinical pharmacology and therapeutics.

[21]  A. D. Rodrigues,et al.  Oxidative metabolism of clarithromycin in the presence of human liver microsomes. Major role for the cytochrome P4503A (CYP3A) subfamily. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[22]  L. Bertilsson,et al.  Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. , 1995, Pharmacogenetics.

[23]  J. Miners,et al.  Identification of human liver cytochrome P450 isoforms mediating secondary omeprazole metabolism. , 1994, British journal of clinical pharmacology.

[24]  J. Miners,et al.  Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. , 1993, British journal of clinical pharmacology.

[25]  K. Brøsen,et al.  Pharmacokinetics of Citalopram in Relation to the Sparteine and the Mephenytoin Oxidation Polymorphisms , 1993, Therapeutic drug monitoring.

[26]  Kaoru Kobayashi,et al.  Simultaneous determination of omeprazole and its metabolites in plasma and urine by reversed-phase high-performance liquid chromatography with an alkaline-resistant polymer-coated C18 column. , 1992, Journal of chromatography.

[27]  T. Andersson,et al.  The Pharmacokinetics of Omeprazole in Humans—A Study of Single Intravenous and Oral Doses , 1990, Therapeutic drug monitoring.

[28]  L. Bertilsson,et al.  Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype , 1990 .

[29]  D. Greenblatt,et al.  Metronidazole Impairs Clearance of Phenytoin but Not of Alprazolam or Lorazepam , 1988, Journal of clinical pharmacology.

[30]  D. Flockhart,et al.  Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism , 2002, Clinical pharmacokinetics.