Disposition of a CYP2C9 Phenotyping Agent, Losartan, Is Not Influenced by the Common 3435C > T Variation of the Drug Transporter Gene ABCB1 (MDR1)

Abstract: Losartan is oxidized to E3174 by cytochrome P450 2C9 (CYP2C9); it has been suggested as a useful probe drug for CYP2C9 activity. It has also been shown to be a substrate for the drug-efflux transporter ATP-binding cassette sub-family B member 1 (ABCB1, MDR1). Both CYP2C9 and ABCB1 genes are polymorphic. The aim of the study was to determine if losartan disposition was influenced by the 3435C > T polymorphism of ABCB1 in healthy persons. These participants (n = 58) whose CYP2C9 genotypes and phenotypes were determined previously were genotyped for 3435C > T polymorphism in ABCB1. The concentrations of losartan and E3174 were compared across genotypes for ABCB1 3435C > T variation. For persons with the ABCB1 3435 CC, CT, TT genotypes, the concentrations (µM, means ± S.D.) of neither losartan (1.76 ± 0.87, 1.68 ± 0.84 and 1.80 ± 0.85, respectively, P = 0.70) nor E3174 (2.97 ± 2.49, 2.53 ± 2.09 and 3.18 ± 2.75, respectively, P = 0.65) were significantly different. These results suggest that ABCB1 3435C > T polymorphism does not have any influence on losartan disposition. Therefore, ABCB1 3435C > T polymorphism is probably not a confounding factor in the prediction of CYP2C9 activity by using losartan as a probe agent.