title: Hydroxylation index of omeprazole in relation to CYP2C19 polymorphism and sex in a healthy Iranian population.
abstract: BACKGROUND
  Polymorphism of CYP2C19 gene is one of the important factors in pharmacokinetics of CYP2C19 substrates. Omeprazole is a proton pump inhibitor which is mainly metabolized by cytochrome P450 2C19 (CYP2C19). The aim of present study was to assess omeprazole hydroxylation index as a measure of CYP2C19 activity considering new variant allele (CYP2C19*17) in Iranian population and also to see if this activity is sex dependent.
  
  
  METHODS
  One hundred and eighty healthy unrelated Iranian individuals attended in this study. Blood samples for genotyping and phenotyping were collected 3 hours after administration of 20 mg omeprazole orally. Genotyping of 2C19 variant alleles *2, *3 and *17 was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and semi-nested PCR methods. Plasma concentrations of omeprazole and hydroxyomeprazole were determined by high performance liquid chromatography (HPLC) technique and hydxroxylation index (HI) (omeprazole/ hydroxyomeprazole) was calculated.
  
  
  RESULTS
  The CYP2C19*17 was the most common variant allele in the studied population (21.6%). Genotype frequencies of CYP2C19*17*17, *1*17, and *2*17 were 5.5%, 28.8% and 3.3% respectively. The lowest and the highest median omeprazole HI was observed in *17*17 and *2*2 genotypes respectively (0.36 vs. 13.09). The median HI of omeprazole in subjects homozygous for CYP2C19*1 was 2.16-fold higher than individuals homozygous for CYP2C19*17 (P < 0.001) and the median HI of CYP2C19*1*17 genotype was 1.98-fold higher than CYP2C19 *17*17 subjects (P < 0.001). However, subjects with CYP2C19*2*17 (median HI: 1.74) and CYP2C19*1*2 (median HI: 1.98) genotypes and also CYP2C19*1*17 (median HI: 0.71) and CYP2C19*1*1 (mean HI: 0.78) did not show any significantly different enzyme activity. In addition, no statistically significant difference was found between women and men in distribution of CYP2C19 genotypes. Furthermore, the hydroxylation index of Omeprazole was not different between women and men in the studied population.
  
  
  CONCLUSIONS
  Our data point out the importance of CYP2C19*2 and CYP2C19*17 variant alleles in metabolism of omeprazole and therefore CYP2C19 activity. Regarding the high frequency of CYP2C19*17 in Iranian population, the importance of this new variant allele in metabolism of CYP2C19 substrates shall be considered.
authors.forename: Maryam
authors.initials: M
authors.lastname: Payan
authors.affiliation: Biopharmaceutics and Pharmacokinetics Division, Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical sciences, Tehran, Iran. rouini@tums.ac.ir.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Rouini
authors.forename: Nader
authors.initials: N
authors.lastname: Tajik
authors.forename: Mohammad Hossein
authors.initials: MH
authors.lastname: Ghahremani
authors.forename: Reza
authors.initials: R
authors.lastname: Tahvilian
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood; D000328:Adult; D000483:Alleles; D000897:Anti-Ulcer Agents / Q000097:blood / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D007492:Iran; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D012737:Sex Factors; D044465:White People; D055815:Young Adult
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D054328:Proton Pump Inhibitors; C049963:5-hydroxymethylomeprazole; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole