Influence of P-glycoprotein on the transplacental passage of cyclosporine

The transfer kinetics of cyclosporine across the dually perfused rat placen ta in the maternal to fetal direction and a possible involvement of P-glyco protein were investigated. The transplacental clearance of cyclosporine in the materno-fetal direction was found to be dependent on the maternal inflo w concentration of cyclosporine. Coadministration of cyclosporine with an e xcess of quinidine or chlorpromazine into the maternal compartment revealed 1.7- and 1.9-fold increase in cyclosporine concentration in the fetal comp artment. In the experiments where quinidine was present both in the materna l and fetal compartments, cyclosporine appeared in the fetal compartment si gnificantly faster, and its amount was three times higher when compared wit h controls. Conversely, quinidine or chlorpromazine did not affect the tran splacental passage of L-[H-3]-glucose. The interference of quinidine with t he metabolism of cyclosporine in the placenta was excluded because only tra ces of M-1 and M-17 metabolites were found in the fetal solutions. Sodium a zide, a mitochondrial respiratory inhibitor, was found to double the rate o f cyclosporine, but not L-[H-3]glucose, passage across the placenta. Our fi ndings indicate that P-glycoprotein pumps cyclosporine out of the trophobla st cells of the rat placenta in the ATP-dependent manner and restricts the passage of cyclosporine across the placental barrier. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.