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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Examination of the Functional Activity of P-glycoprotein in the Rat Placental Barrier Using Rhodamine 123

Departments of Pharmacology and Toxicology (P.P., F.S., Z.F., A.L., M.N.), Analytical Chemistry (H.S.), and Biomedical Sciences (M.K., V.S.), Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic; and Institute of Experimental Biopharmaceutics, Joint Research Center of Academy of Sciences of the Czech Republic and PRO.MED.CS Praha a.s. (Mi.N.), Hradec Králové, Czech Republic

Rhodamine 123 (Rho123), a model substrate of P-glycoprotein (P-gp), was used to evaluate the functional activity of P-gp efflux transporter in the rat placental barrier. The dually perfused rat-term placenta method was used. In our experiments, the materno-fetal transplacental passage of Rho123 did not meet the criteria of the first-order pharmacokinetics, suggesting an involvement of transporter-mediated process. Inhibitors of P-gp, such as [3'-keto-Bmt¹]-[Val²]-cyclosporine (PSC833), cyclosporine (CsA), quinidine, and chlorpromazine, increased significantly the materno-fetal transplacental passage of Rho123 in the experiments under steady-state conditions. On the other hand, PSC833, CsA, and quinidine decreased the feto-maternal passage of Rho123. Similarly, in the experiments carried out under nonsteady-state conditions, CsA accelerated the passage of Rho123 in the materno-fetal direction and decreased its passage in the opposite direction. Feto-maternal transplacental clearances of Rho123 were found to be considerably higher than those in the materno-fetal course. Potent P-gp inhibitors, such as PSC833 or CsA, partially canceled the asymmetry. Negligible metabolism of Rho123 into its major demethylated metabolite rhodamine 110 was observed in the rat placenta. Expression of P-gp genes was detected using immunohistochemical, Western blotting, and reverse transcription-polymerase chain reaction methods preferentially in the second rat syncytiotrophoblast layer. In conclusion, these data suggest that P-gp limits the entry of Rho123 into fetuses and at the same time it accelerates the feto-maternal elimination of the model compound. Therefore, it seems plausible that pharmacokinetics of xenobiotics in the rat placental barrier could be controlled by P-gp in both directions.

Address correspondence to: Dr. Petr Pavek, Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy, Heyrovského 1203, Hradec Králové, CZ-500 05, Czech Republic. E-mail: pavek{at}faf.cuni.cz

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