Possible Interethnic Differences in Omeprazole Pharmacokinetics

Abstract

Considerable ethnic differences have been reported in the incidence of the poor metaboliser (PM) genotype of cytochrome P450 (CYP) 2C19. The frequency of this genotype was found to be much higher in Oriental persons (13-23%) than in American or European populations (3-5%). There are, however, no valid data published for Arabic subjects. The present study was conducted to evaluate pharmacokinetic parameters of omeprazole after a single dose in healthy Jordanian Arabic subjects and to compare the results with data published for other populations. Seventy-four healthy male Jordanian Arabic volunteers contributed to the study, which was performed at Al Essra Hospital in Amman, Jordan. After an overnight fast, omeprazole was administered as a single Losec 20mg capsule. A total of 20 blood samples were collected over a 10-hour period after administration. Omeprazole pharmacokinetic parameters were determined from the plasma concentration-time profiles using the WinNonlin software. Kolmogorov-Smirnov's test and probit plots of omeprazole area under the plasma concentration-time curve (AUC) data were used to analyse the frequency distribution of phenotypic data. The mean pharmacokinetic parameters and their corresponding coefficient of variation (CV%) for peak plasma concentration (Cmax), AUC from time zero to infinity (AUCinfinity), time to reach Cmax (tmax), apparent oral clearance (CL/F) and elimination half-life (t(1/2)) were 314.96 ng/mL (56%), 923.2 ng . h/mL (108.6%), 2.1h (44%), 0.66 L/h/kg (92%) and 1.5 h (56.6%), respectively. Interindividual differences in the current study were high for all pharmacokinetic parameters, yet comparable to CVs reported in nonphenotyped subjects identified within other ethnic groups (40.3-159% for AUC and 39-48.2% for Cmax). The frequency distribution of all parameters, particularly the AUC, was shown to be trimodal. This has proposed the presence of three distinct phenotypes, designated as extensive metabolisers (EMs), slow-extensive metabolisers (SEMs), and PMs, with corresponding frequency of 36.5%, 39.2% and 24.3%, respectively. After stratification, the relative mean AUCs of omeprazole in EMs, SEMs and PMs were 1 : 2.7 : 9.3 (all p < 0.001). Accordingly, the CL/F of omeprazole showed a ratio of 9.8 : 3.6 : 1 for three phenotype groups, respectively. For other pharmacokinetic parameters including Cmax, t1/2, AUC normalised for bodyweight (AUCN), Cmax/dose and AUC/dose, there were also significant differences between the three groups. The current pharmacokinetic study revealed that the majority of the Jordanian Arabics seemed to be more properly classified within the EM phenotype. More specifically, the observed metabolic rates of heterozygous and homozygous Jordanian Arabic EMs were more comparable to those of Caucasian EMs than Oriental EMs. Consequently, higher dosage requirements can be expected among most of the Jordanian Arabics. Yet, the incidence of PMs is significant and they seemed to exhibit a similar pharmacokinetic pattern to Chinese PMs in terms of long-term exposure (clearance and AUC) as well as short-term exposure (Cmax) parameters, after adjustment for dose and bodyweight. Therefore, further clinical application of CYP2C19 polymorphism is anticipated in Jordanian Arabic mixed population, particularly if long-term use of omeprazole is intended.