Transplacental pharmacokinetics of glyburide, rhodamine 123, and BODIPY FL prazosin: effect of drug efflux transporters and lipid solubility.
Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are the most abundantly expressed ATP-binding cassette (ABC) drug transporters in the placenta. They recognize a large, partly overlapping spectrum of chemically unrelated compounds and affect their transplacental passage. In this study we investigate the effect of Bcrp and P-gp on the transplacental pharmacokinetics of their specific and common substrates employing the technique of dually perfused rat placenta. We show that the clearance of rhodamine 123 (P-gp substrate), glyburide (BCRP substrate) and BODIPY FL prazosin (P-gp and BCRP substrate) in fetal-to-maternal direction is 11, 11.2 and 4 times higher, respectively, than that in the maternal-to-fetal direction. In addition, all of these substances were found to be transported from the fetal compartment even against concentration gradient. We thus demonstrate the ability of placental ABC transporters to hinder maternal-to-fetal and accelerate fetal-to-maternal transport in a concentration-dependent manner. However, by means of pharmacokinetic modeling we describe the inverse correlation between lipid solubility of a molecule and its active transport by placental ABC efflux transporters. Therefore, in the case of highly lipophilic substrates, such as BODIPY FL prazosin in this study, the efficacy of efflux transporters to pump the molecule back to the maternal circulation is markedly limited.
Cygalova
Lenka Hahnova
LH
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Prague, Czech Republic.
Hofman
Jakub
J
Ceckova
Martina
M
Staud
Frantisek
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001896:Boron Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005905:Glyburide / Q000737:chemistry / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry*; D008431:Maternal-Fetal Exchange; D010477:Perfusion; D010920:Placenta / Q000378:metabolism*; D011224:Prazosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D011247:Pregnancy; D051381:Rats; D020112:Rhodamine 123 / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; C412306:BODIPY-FL prazosin; D001896:Boron Compounds; D008055:Lipids; D020112:Rhodamine 123; D005905:Glyburide; D011224:Prazosin