title: Evaluation of rat in vivo fetal-to-maternal transfer clearances of various xenobiotics by umbilical perfusion.
abstract: It is important to address the tissue permeability of drugs, particularly in tissues that have a blood-tissue barrier, in terms of both lipophilicity and the contribution of transporters. Here, we employed umbilical perfusion in rats to evaluate in vivo fetal-to-maternal transfer clearances of various xenobiotics. We measured fetal-to-maternal clearance (CLfm ) of 23 compounds, which have a broad range of lipophilicity. Drugs for which CLfm was more than 300 µL/(mL min) belonged exclusively to Biopharmaceutical Drug Disposition Classification System (BDDCS) class 1 (highly permeable) and those for which CLfm was less than 50 µL/(mL min) belonged exclusively to BDDCS class 3 (poorly permeable). For most drugs, CLfm values were broadly consistent with lipophilicity. However, CLfm of digoxin was saturable and was inhibited by verapamil, suggesting that P-glycoprotein (P-gp)-mediated efflux has a substantially effect on measured clearance. CLfm of mitoxantrone continued to increase slightly at high concentrations of mitoxantrone, but placental-to-maternal clearance of mitoxantrone was saturable, implying that Bcrp1 contributes to mitoxantrone efflux across the placenta. Thus, we measured CLfm by umbilical perfusion and examined the relationship between CLfm and lipophilicity of xenobiotics. Fetal-to-maternal transport clearances measured in this study will be helpful to understand the characteristics of the blood-placental barrier.
authors.affiliation: Keio University, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishimura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takanohashi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tomi
authors.forename: Miho
authors.initials: M
authors.lastname: Horikoshi
authors.forename: Kei
authors.initials: K
authors.lastname: Higuchi
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.forename: Emi
authors.initials: E
authors.lastname: Nakashima
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D005260:Female; D007700:Kinetics; D008431:Maternal-Fetal Exchange; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004364:Pharmaceutical Preparations; D015262:Xenobiotics
keywords: active transport; biopharmaceutics classification system (BCS); clearance; drug transport; efflux pumps; kinetics; log P; placenta; pregnancy