Pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes.
BACKGROUND
PPIs are widely used in peptic diseases, and this paper is to investigate the kinetic characteristics of a new PPI ilaprazole in Chinese healthy subjects and the association with CYP3A5 and CYP2C19 polymorphisms.


METHODS
21 subjects were selected and treated with 10mg ilaprazole according to their CYP3A5*3 genotypes (including 7 of CYP3A5*1/*1, 7 of *1/*3, and 7 of *3/*3). The plasma concentrations of ilaprazole and its metabolites were monitored by LC-MS/MS method.


RESULTS
The C(max), AUC((0-6)), AUC((0-48)) and AUC((0-infinity)) of ilaprazole were all significantly different across the 3 CYP3A5 genotypes (including 4 of CYP3A5*1/*1, 4 of *1/*3, 3 of *3/*3; P<0.05) in CYP2C19 wild-type subjects (CYP2C19 wt/wts), similar variety of C(max) and AUC((0-6)) among CYP3A5 genotypes (including 3 of CYP3A5*1/*1, 3 of *1/*3, 4 of *3/*3; P<0.05) were also observed in CYP2C19 heterozygous subjects (CYP2C19 wt/mts). The sulfoxidation metabolic index (measure of collective CYP3A activity) indicates that the CYP3A5*1/*1, (high-expressers), *1/*3, (low-expressers), and *3/*3 (no-expressers) groups have medium, lowest and highest activities on ilaprazole metabolism, inconsistent with genotype-based CYP3A5 enzymatic activity. Further analysis showed no correlation between ilaprazole metabolism and CYP2C19 genotypes, evidenced by that the AUC((0-infinity)) of ilaprazole from either CYP3A5*1/*1 or CYP3A5*1/*3 groups was much higher in CYP2C19 wt/wts (n=4) than that in CYP2C19 wt/mts (n=3) (P<0.001), but the C(max) and AUC((0-6)) of ilaprazole from CYP3A5*3/*3 groups, were significantly lower in CYP2C19 wt/wts (n=3) compared to CYP2C19 wt/mts (n=4) (P<0.01).


CONCLUSIONS
There was no demonstrated relationship between ilaprazole metabolism and CYP3A5 polymorphisms.
Li
Yalin
Y
Institute of Clinical Pharmacology, Central South University, Changsha, China.
Zhang
Wei
W
Guo
Dong
D
Zhou
Gan
G
Zhou
Honghao
H
Xiao
Zhousheng
Z
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001562:Benzimidazoles / Q000097:blood / Q000493:pharmacokinetics*; D002681:China; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000493:pharmacokinetics*; D013454:Sulfoxides / Q000097:blood / Q000493:pharmacokinetics*
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D013454:Sulfoxides; C119615:ilaprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A