Effects Of CYP2C19 Genetic Polymorphism On The Pharmacokinetics And Pharmacodynamics Of Rabeprazole And Omeprazole In Chinese Subjects

Introduction S-mephenytoin-4-hydroxylase (CYP2C19) is a genetically determined enzyme. The major mutation of CYP2C19 in Chinese subjects were CYP2C19ml and CYP2C19m2. In population, its phenotypes have poor metabolizer and extensive metabolizer. When CYP2C19 is main metabolism enzyme of a drug, the pharmacokinetics of the drug are different between PMs and EMs. Proton pump inhibitors (PPIs) were metabolized mainly via CYP2C19 and CYP3A4. omeprazole were metabolized mainly via CYP2C19 and CYP3A4, but rabeprazole has been reported to be metabolized mainly via a non-enzymatic pathway, with only minor CYP2C19 and CYP3A4 involvement. The pharmacokinetics of rabeprazole are assumed to be less influenced by the CYP2C19 phenotype. Now. there was little study on the pharmacokinetics and pharmacodynamics of omeprazole and rabeprazole. It is not clear whether the pharmacokinetics and pharmacodynamics of rabeprazole depend on the CYP2C19 genotype status in Chinese people. And the incident of PM for CYP2C19 in Chinese population is very high (15-17%). It is more valuable to research the effects of CYP2C19 genetic polymorphism on the metabolism of rabeprazole in Chinese people.Besides the CYP2C19 polymorphism, the absorption and distribute could affect the pharmacokinetics of rabeprazole. Especially, absorption was very important. There was little study on the aninmal model and CaCo-2 cells about the absorption characteristics of rabeprazole.Objective To investigate the acid inhibitory effects and serum levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes in Chinese Han healthy subjects by self-control design and explore the absorption characteristics of rabeprazole from various intestinal segments by the rat everted gut sac system, in situ perfusing methods in rat and CaCo-2 cells system.Methods The CYP2C19 genotype status (CYP2C19mi and CYP2C19m2) of Chinese Han healthy volunteers were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Twenty healthy subjects were voluntary to participate in the study. There were seven homozygous extensive metabolizers, six heterozygous extensive metabolizers and seven poor metabolizers. All subjects were H. pylori-negative .which were determined by serology and l3C-urea breath test. All healthy volunteers took a daily dose of 20 mg of omeprazole or rebaprazole for 8 days. On postdose days 1 and 8, the profiles of intragastric pH were monitored for 24 hours by Digitrapper pH and the serum concentrations of omeprazole or rebaprazole were measured by high performance liquid chromatography.The rat everted gut sac system and in-situ perfusing methods was used. The Krebs solution contained 20 mg/L rabeprazole. The solution inside sac and of Krebs containing rabeprazole were collected . CaCo-2 cells were incubated for 0, 5,10,15 and 20 min in humidified atmosphere of 5% CO2 at 37 °C. The drug concentration of rabeprazole was dertermined by HPLC. Results(1) The frequence of CYP2C19 PM in 110 Chinese subjects was 11%.(2) Effects of CYP2C19 genetic polymorphism on the metabolism of rabeprazole and intragastric pH : The mean AUC values for rabeprazole after a single dose differed among the three different genotype groups, with a relative ratio of 1.0, 1.3 and 1.8 in thehomEM, hetEM and PM groups, respectively; and with a relative ratio of 1.0, 1.1 and 1.7 after repeated doses, respectively. The mean AUC values for rabeprazole after a single and repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM, hetEM and PM groups. No significant increase in the mean AUC values for rabeprazole from single to repeated doses was observed in any of the three different genotype groups. The Cmax values were significantly different between the homEM and PM groups, hetEM and PM groups, so do that after repeated doses. The Tmax and T1/2 among three groups have no significant difference on dl and d8. No significant differences in intragastric pH median, pH>4 total time and the pH>4 time percentage of 24 hours were observed among the three different genotype groups after a single dose or repeated doses. No significant increments in intragastric pH values from single to repeated doses were also observed in the three different genotype groups.(3) Effects of CYP2C19 genetic polymorphism on the metabolism of omeprazole and intragastric pH : The mean AUC values for omeprazole after a single dose differed among the three different genotype groups, with a relative ratio of 1.0, 1.1 and 4.2 in the homEM, hetEM and PM groups, respectively; and with a relative ratio of 1.0, 1.3 and 3.3 after repeated doses, respectively. After a single and repeated doses of omeprazole, mean AUC values were significantly different between the homEM and PM groups, hetEM and PM groups but not between the homEM and hetEM. The significant increase in the mean AUC values for omeprazole from single to repeated doses was observed in homEM and hetEM groups. Cmax and Tm were significantly different between the homEM and PM groups, hetEM and PM groups. The intragastric pH values of omeprazole were significantly different among the three groups.(4) The acid-inhibitory effection between omeprazole and rabeprazole: After a single...