P-glycoprotein restricted transport of nimodipine across blood-brain barrier

AIM: To examine whether the transport of nimodipine (NMD) from the circulating blood into the brain is restricted by P-glycoprotein (P-gp) in rat brain capillary endothelial cells (BCEC). METHODS: When cells reached confluence, a time course of NMD uptake was recorded by incubation with a medium containing NMD 10 mg/L at 37 °C. Effects of various agents in the steady-state uptake of NMD were tested by co-administration with NMD and each compound to cells at 37 °C for 90 min. The uptake of NMD was measured for 90 min. Effects of P-gp inhibitors on the efflux of NMD from primary cultured BCEC were studied by administration of erythromycin, clarithromycin, cyclosporin A (CsA), and Hanks' solution after the accumulation of NMD by BCEC at 37 °C for 90 min. RESULTS: The uptake of NMD by primary cultured rat BCEC was time-dependent, and the steady-state uptake of NMD was increased in the presence of several substrates of P-gp in BCEC. The steady-state uptake was also significantly increased (P<0.01) when celluar ATP was depleted by treatment with sodium azide. Furthermore, efflux of NMD from BCEC was inhibited by erythromycin, clarithromycin, and CsA. CONCLUSION: The permeability of NMD into the brain is restricted by P-gp and increased by co-administration with P-gp inhibitors.