Omeprazole as a CYP2C19 marker in Chinese subjects: assessment of its gene-dose effect and intrasubject variability.
The objective of this study was to determine the reliability of omeprazole as a marker for CYP2C19 activity in Chinese subjects. In 27 healthy male Chinese subjects, the CYP2C19 phenotype was first determined with the standard mephenytoin hydroxylation index (HI) method. Subsequently, the subjects were randomized in a three-way crossover manner to receive an oral 40-mg dose from each of three omeprazole formulations (as part of a bioequivalence study). Multiple blood samples were obtained over 12 hours, and plasma concentrations of omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone were determined by a high-performance liquid chromatography (HPLC) method. Individual CYP2C19 genotype was determined by the polymerase chain reaction/restriction fragment length polymorphism method. To assess the specificity for CYP2C19 activity, the hydroxylation metabolic ratio (MR) of omeprazole (AUC(omeprazole)/AUC(5-hydroxyomeprazole)) was compared to mephenytoin HI and related to CYP2C19 genotype status. The inter- and intrasubject variabilities of MR were also calculated, and their magnitudes were compared. The intersubject MR varied more than 20 fold. Among the subjects, there was a gene-dose effect, and the mean MR was 1.76, 3.45, and 33.08, respectively, in the homozygous extensive metabolizers (wt/wt, n = 9), heterozygous extensive metabolizers (wt/m1 or wt/m2, n = 10), and poor metabolizers (m1/m1 or m1/m2, n = 7). However, the coefficients of variation for intrasubject MR only ranged from 4.5% to 33.7% over the three periods with the three formulations. The phenotype based on MR was concordant with HI. In view of the clear gene-dose effect, concordance with mephenytoin HI, and low intrasubject variability, omeprazole MR following a 40-mg oral dose can be considered as a specific and sensitive marker for CYP2C19 activity in Chinese subjects.
Yin
Ophelia Q P
OQ
School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Tomlinson
Brian
B
Chow
Albert H L
AH
Waye
Mary M Y
MM
Chow
Moses S S
MS
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D018628:Gene Dosage; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D009853:Omeprazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012016:Reference Values
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D004791:Enzyme Inhibitors; C040450:omeprazole sulfone; C049963:5-hydroxymethylomeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin