Keio University, Minato-ku, Tokyo 105-8512, Japan.
J Pharm Sci. 2013 Sep;102(9):3356-63. doi: 10.1002/jps.23551. Epub 2013 Apr 25.
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.
药物的组织通透性很重要，特别是对于具有血组织屏障的组织，要考虑亲脂性和转运体的作用。在这里，我们采用大鼠脐带灌注的方法，评估了各种外源性物质在体内的胎儿向母体转移清除率。我们测量了 23 种具有广泛亲脂性的化合物的胎儿向母体清除率（CLfm）。CLfm 大于 300µL/（mL min）的药物均属于生物药剂学药物处置分类系统（BDDCS）类别 1（高渗透性），而 CLfm 小于 50µL/（mL min）的药物均属于 BDDCS 类别 3（低渗透性）。对于大多数药物，CLfm 值与亲脂性广泛一致。然而，地高辛的 CLfm 是饱和的，并被维拉帕米抑制，表明 P 糖蛋白（P-gp）介导的外排对测量的清除率有很大影响。米托蒽醌的 CLfm 在米托蒽醌的高浓度下继续略有增加，但米托蒽醌的胎盘向母体清除率是饱和的，这意味着 Bcrp1 有助于米托蒽醌从胎盘的外排。因此，我们通过脐带灌注测量 CLfm，并研究 CLfm 与外源性物质亲脂性之间的关系。本研究中测量的胎儿向母体转运清除率将有助于了解血胎盘屏障的特征。
