Evaluation of rat in vivo fetal-to-maternal transfer clearances of various xenobiotics by umbilical perfusion

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 (CL_fm) of 23 compounds, which have a broad range of lipophilicity. Drugs for which CL_fm was more than 300 μL/(mL min) belonged exclusively to Biopharmaceutical Drug Disposition Classification System (BDDCS) class 1 (highly permeable) and those for which CL_fm was less than 50 μL/(mL min) belonged exclusively to BDDCS class 3 (poorly permeable). For most drugs, CL_fm values were broadly consistent with lipophilicity. However, CL_fm of digoxin was saturable and was inhibited by verapamil, suggesting that P-glycoprotein (P-gp)-mediated efflux has a substantially effect on measured clearance. CL_fm 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 CL_fm by umbilical perfusion and examined the relationship between CL_fm 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.