Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
J Pharm Sci. 2012 Jul;101(7):2606-15. doi: 10.1002/jps.23174. Epub 2012 Apr 26.
The purpose of the present study is to examine the long-lasting inhibition of intestinal organic anion transporting polypeptides (Oatps) by cyclosporin A (CsA) in rats using fexofenadine (FEX) as a probe drug. We examined the pharmacokinetics of FEX after its intravenous or oral administration to rats at 3 or 24 h after the oral administration of CsA. When FEX was administered at 3 h after the administration of CsA, its plasma concentration increased regardless of whether it was administered intravenously or orally. When FEX was intravenously administered at 24 h after the oral administration of CsA, its plasma concentration was increased; however, that observed after its oral administration was not significantly different from the vehicle-treated control. When FEX was administered at 3 h after the administration of CsA, the hepatic availability (F(h)) and the fraction absorbed in the intestine as an unchanged form (F(a)·F(g)) of FEX were increased, resulting in increased bioavailability (=F(a)·F(g)·F(h)). At 24 h after the administration of CsA, the F(h) of FEX was increased, whereas its bioavailability was decreased, suggesting that its F(a)·F(g) was decreased because of the long-lasting inhibition. In conclusion, CsA has long-lasting inhibitory effects on Oatps in the rat intestine as well as in the liver.
本研究旨在通过以非索非那定为探针药物，研究环孢素 A（CsA）对大鼠肠道有机阴离子转运多肽（Oatps）的长期抑制作用。我们检测了 CsA 口服给药 3 或 24 小时后大鼠静脉或口服给予非索非那定后的药代动力学。当 CsA 给药 3 小时后给予非索非那定时，无论静脉或口服给药，其血浆浓度均增加。当 CsA 口服给药 24 小时后静脉给予非索非那定时，其血浆浓度增加；然而，口服给药后的观察结果与未处理的对照组无显著差异。当 CsA 给药 3 小时后给予非索非那定时，非索非那定的肝可用性（F(h)）和作为未变化形式吸收在肠中的分数（F(a)·F(g)）增加，导致生物利用度增加（=F(a)·F(g)·F(h)）。在 CsA 给药 24 小时后，非索非那定的 F(h)增加，但其生物利用度降低，表明其 F(a)·F(g)减少，因为存在长期抑制作用。总之，CsA 对大鼠肠道和肝脏中的 Oatps 具有长期抑制作用。
