INFLUENCE OF ABCB1 GENETIC POLYMORPHISMS ON THE PHARMACOKINETICS OF LEVOSULPIRIDE IN HEALTHY SUBJECTS

The purposes of this study were to clarify the involvement of P-glycoprotein in the absorption of levosulpiride in knockout mice that lack the Abcb1a/1b gene, and to evaluate the relationship between genetic polymorphisms in ABCB1 (exon 12, 21 and 26) and levosulpiride disposition in healthy subjects. The plasma and brain samples were obtained after oral administration (10 mu g/g) of levosulpiride to abcb1a/1b(-/-) and wild-type mice (n=3 similar to 6 at each time point). The average brain-to-plasma concentration ratio and blood-brain barrier partitioning of levosulpiride were 2.3- and 2.0-fold higher in Abcb1a/1b(-/-) mice than in wild-type mice, respectively. A total of 58 healthy Korean volunteers receiving a single oral dose of 25 mg levosulpiride participated in this study. The subjects were evaluated for polymorphisms of the ABCB1 exon 12 C1236T, exon 21 G2677A/T (Ala893Ser/Thr) and exon 26 C3435T using polymerase chain reaction restriction fragment length polymorphism. The PK parameters (AUC(0-4h), AUC(0-infinity) and C-max) of ABCB1 2677TT and 3435TT subjects were significantly higher than those of subjects with at least one wild-type allele (P<0.05). The results indicate that levosulpiride is a P-glycoprotein substrate in vivo, which is supported by the effects of SNPs 2677G>A/T in exon 21 and 3435C>T in exon 26 of ABCB1 on levosulpiride disposition. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.