Population pharmacokinetics of levosulpiride with genetic polymorphisms of MDR1 gene in healthy subject

HY Cho1, YB Lee2. 1CHA University, College of Pharmacy and CHA Bundang Medical Center, Republic of Korea, 2Chonnam National University, College of Pharmacy and Institute of Bioequivalence and Bridging Study, Republic of Korea

Aims: The aim of this study was to evaluate the influence of multi-drug resistance (MDR) 1 genetic polymorphisms on the population pharmacokinetics (PPK) of levosulpiride in healthy Korean subjects. Methods: A single oral dose of 25-mg levosulpiride was orally administered to 58 healthy male subjects. The serum concentrations of levosulpiride were measured up to 36 hr using HPLC method. We determined the polymorphic alleles of MDR1 exon 12 C1236T, exon 21 G2677T, and exon 26 C3435T in each subjects using a polymerase chain reaction-restriction fragment length polymorphism. The PPK model was applied using a nonlinear mixed effects modeling method, and explored the possible influence of genetic polymorphisms in MDR1 C1236T, G2677T, and C3435T on the PPK of levosulpiride. Results: A one-compartment model with first-order absorption and lag time well characterized the serum concentration data. Significant covariates for levosulpiride clearance (CL/F) were genetic polymorphisms of MDR1 G2677T and C3435T. In the exon 21 2677TT and 26 3435TT genotype groups, the concentrations of levosulpiride were significantly higher than those of other groups (GG and CC) (P<0.05). However, statistically significant differences could only be observed among the genotype groups in exon 21 for the AUC0- ∞ and AUC0-2h, area under the concentration-time curve up to 2 hr, which represents the absorption phase of levosulpiride (P=0.040 and P=0.033, Kruskal-Wallis Test). However, no significant differences were found among MDR1 C1236T CC, CT and TT groups with regard to the PK parameters of levosulpiride. Conclusions: This study shows that genetic polymorphisms of MDR1 exon 21 G2677T and exon 26 C3435T might explain the variability in PK of levosulpiride in the Korean population.