Transplacental pharmacokinetics of glyburide, rhodamine 123, and BODIPY FL prazosin: effect of drug efflux transporters and lipid solubility
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
19779128
DOI
10.1124/jpet.109.160564
PII: S0022-3565(24)45572-9
Knihovny.cz E-resources
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
- ATP-Binding Cassette Transporters metabolism MeSH
- Biological Transport MeSH
- Glyburide chemistry pharmacokinetics MeSH
- Rats MeSH
- Lipids chemistry MeSH
- Maternal-Fetal Exchange MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism MeSH
- Perfusion MeSH
- Placenta metabolism MeSH
- Prazosin analogs & derivatives chemistry pharmacokinetics MeSH
- Rhodamine 123 chemistry pharmacokinetics MeSH
- Solubility MeSH
- Boron Compounds chemistry pharmacokinetics MeSH
- Substrate Specificity MeSH
- In Vitro Techniques MeSH
- Pregnancy MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
- ATP-Binding Cassette Transporters MeSH
- Abcg2 protein, rat MeSH Browser
- BODIPY-FL prazosin MeSH Browser
- Glyburide MeSH
- Lipids MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 MeSH
- Prazosin MeSH
- Rhodamine 123 MeSH
- Boron Compounds MeSH
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.
References provided by Crossref.org
Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine
