Pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes

• Published in: Clinica chimica acta Vol. 391; no. 1-2; pp. 60 - 67
• Main Authors: Li, Yalin, Zhang, Wei, Guo, Dong, Zhou, Gan, Zhou, Honghao, Xiao, Zhousheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2008
• Subjects: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Alleles; Aryl Hydrocarbon Hydroxylases - genetics; Benzimidazoles - blood; Benzimidazoles - pharmacokinetics; China; CYP2C19; CYP3A5; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A - genetics; Genetic polymorphisms; Genotype; Humans; Ilaprazole; Male; Pharmacokinetics; Polymorphism, Genetic; Proton Pump Inhibitors - pharmacokinetics; Sulfoxides - blood; Sulfoxides - pharmacokinetics; SNPs; CYP2C19 wt/mts; Ilaprazole; CYP2C19; Pharmacokinetics; CYP3A5; Genetic polymorphisms; CYP2C19 wt/wts; PPIs
• ISSN: 0009-8981; 1873-3492
• DOI: 10.1016/j.cca.2008.02.003

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. 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. The Cmax, AUC(0–6), AUC(0–48) and AUC(0–∞) 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 Cmax 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–∞) 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 Cmax 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). There was no demonstrated relationship between ilaprazole metabolism and CYP3A5 polymorphisms.