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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 305; no. 3; pp. 1239 - 1250
• Main Authors: Pavek, Petr, Staud, Frantisek, Fendrich, Zdenek, Sklenarova, Hana, Libra, Antonin, Novotna, Martina, Kopecky, Martin, Nobilis, Milan, Semecky, Vladimir
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.06.2003
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological Transport - drug effects; Chlorpromazine - pharmacology; Cyclosporins - pharmacology; Drug Interactions; Female; Fluorescent Dyes - pharmacokinetics; Placenta - metabolism; Pregnancy; Quinidine - pharmacology; Rats; Rats, Wistar; Rhodamine 123 - pharmacokinetics; Sodium Azide - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.048470

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-Bmt 1 ]-[Val 2 ]-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.