Examination of the functional activity of P-glycoprotein in the rat placental barrier using rhodamine 123.
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.
Pavek
Petr
P
Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy, Heyrovského 1203, Hradec Králové, CZ-500 05, Czech Republic. pavek@faf.cuni.cz
Staud
Frantisek
F
Fendrich
Zdenek
Z
Sklenarova
Hana
H
Libra
Antonin
A
Novotna
Martina
M
Kopecky
Martin
M
Nobilis
Milan
M
Semecky
Vladimir
V
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002746:Chlorpromazine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000493:pharmacokinetics*; D019810:Sodium Azide / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D005456:Fluorescent Dyes; D020112:Rhodamine 123; D019810:Sodium Azide; D011802:Quinidine; C070272:valspodar; D002746:Chlorpromazine