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


CONCLUSIONS
The permeability of NMD into the brain is restricted by P-gp and increased by co-administration with P-gp inhibitors.
Zhang
Li
L
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Liu
Xiao-Dong
XD
Xie
Lin
L
Wang
Guang-Ji
GJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D002196:Capillaries; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply; D016572:Cyclosporine / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004730:Endothelium, Vascular / Q000378:metabolism*; D004917:Erythromycin / Q000494:pharmacology; D009553:Nimodipine / Q000493:pharmacokinetics*; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D009553:Nimodipine; D004917:Erythromycin; D016572:Cyclosporine