Delavirdine is Substrate of Bcrp and P‐gp

Abstract

IntroductionDelavirdine is an antiretroviral drug characterized by a brain/plasma pharmacokinetic disequilibrium where the cerebrospinal fluid concentration, a surrogate for unbound brain concentration, in humans is approximately 5‐fold lower than corresponding unbound plasma concentrations (Rescriptor package insert). A previous report using Caco‐2 cells suggested that delavirdine is not a P‐gp substrate (Störmer, et al., 2002). Breast cancer resistance protein (Bcrp) was therefore investigated as a mechanism that could limit penetration of delavirdine into the CNS.Material and MethodsMDCK‐mBcrp and MDCK‐MDR1 cells were used to assess transport of delavirdine by each respective transporter. The bidirectional permeability of delavirdine was investigated as a function of time and in the absence or presence of inhibitor. Assay samples were then subject to liquid chromatography/mass spectrometry.ResultsDelavirdine demonstrated asymmetric flux by the MDCK‐mBcrp cells that was time dependent. Interestingly, time dependent asymmetric flux of delavirdine was also observed in the MDCK‐MDR1 cells. The asymmetric flux of delavirdine in both cell lines could further be brought to near unity in the presence of inhibitors of Bcrp and MDR1 (Ko143 and LY335979, respectively).ConclusionThe results established the asymmetric transport of delavirdine by P‐gp and mBcrp. The asymmetric transport of delavirdine by P‐gp and mBcrp was time dependent and inhibitable. Collectively, both transporters likely limit the CNS penetration of delavirdine observed in vivo.Störmer E, et al. Differential modulation of P‐glycoprotein expression and activity by non‐nucleoside HIV‐1 reverse transcriptase inhibitors in cell culture. Pharm Res. 19(7):1038‐45, 2002.