The effect of probenecid and MK-571 on the feto-maternal transfer of saquinavir in dually perfused human term placenta.
Human placenta, particularly the blood-placenta barrier, with various transporters has crucial role to protect the fetus and, on the other hand, to facilitate movement of compounds towards the fetal circulation. This study aimed to characterize the role of basal transporters of the syncytiotrophoblast, which appear to be yet less studied, in the fetal-to-maternal transfer of saquinavir by use of dually perfused human placentas. A dual perfusion of human placenta was performed to study effect of MK-571 and probenecid, inhibitors of the MRP1 and OATP transporters, expressed in the basal trophoblast membrane, on the transfer of saquinavir. The fetal-to-maternal placental transfer of saquinavir in the control group as measured by TPT(AUC)% (absolute fraction of the dose crossing placenta) was 14.0%, which is 73% less than the transfer of the freely diffusible antipyrine. The two inhibitors, MK-571 and probenecid caused a non-significant (P = 0.34 for ANOVA) reduction of 43% and 24%, respectively, in the mean amount of saquinavir transferred from the fetal to the maternal side. MK-571 also somewhat (by 31%) reduced the TPT(AUC)% of antipyrine, but this finding did not reach statistical significance (P = 0.25). Neither of the employed inhibitors had an effect on the placental transfer index of saquinavir transfer (P = 0.77). The present results indicated lack of significant effect by MK-571 and probenecid on the fetal-to-maternal transfer of saquinavir and suggest that MRP1 and, possibly, OATP2B1 do not play a significant role in the fetal-to-maternal transfer of saquinavir.
Rahi
Mea Melissa
MM
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Finland. melissa.rahi@tyks.fi
Heikkinen
Tuija Maarit
TM
Hakala
Kristo Eerik
KE
Laine
Kari Petri
KP
D000983:Antipyrine / Q000493:pharmacokinetics; D001692:Biological Transport; D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange / Q000187:drug effects*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D010477:Perfusion; D010920:Placenta / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011339:Probenecid / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D019258:Saquinavir / Q000493:pharmacokinetics*; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism
D000983:Antipyrine; D017320:HIV Protease Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D011339:Probenecid; D011422:Propionates; D011804:Quinolines; D019258:Saquinavir; C059141:verlukast; C421109:multidrug resistance-associated protein 1