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 degrees 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 degrees 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 degrees 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 cellular 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.