Lau Yvonne Y, Wu Chi-Yuan, Okochi Hideaki, Benet Leslie Z
Department of Biopharmaceutical Sciences, University of California, San Francisco, San Francisco, CA 9414-0446, USA.
J Pharmacol Exp Ther. 2004 Mar;308(3):1040-5. doi: 10.1124/jpet.103.061770. Epub 2003 Nov 21.
The disposition of digoxin and the influence of the organic anion transporting polypeptide (Oatp)2 inhibitor rifampicin and the P-glycoprotein (P-gp) inhibitor quinidine on its hepatic disposition were examined in the isolated perfused rat liver. Livers from groups of rats were perfused in a recirculatory manner after a bolus dose of digoxin (10 microg), a dual substrate for Oatp2 and P-gp as well as CYP3A. Perfusions of digoxin were also examined in groups of rats in the presence of the inhibitors: rifampicin (100 microM) or quinidine (10 microM). In all experiments, perfusate samples were collected for 60 min. Digoxin and its primary metabolite were determined in perfusate and liver by liquid chromatography/mass spectrometry. The area under the curve (AUC) from 0 to 60 min was determined. The AUC +/- S.D. of digoxin was increased from control (3880 +/- 210 nM x min) by rifampicin (5200 +/- 240 nM x min; p < 0.01) and decreased by quinidine (3220 +/- 340 nM x min; P < 0.05). It is concluded that rifampicin limits the hepatic entrance of digoxin and reduced the hepatic exposure of digoxin to CYP3A by inhibiting the basolateral Oatp2 uptake transport, whereas quinidine increased the hepatic exposure of digoxin to CYP3A by inhibiting the canalicular P-gp transport. These data emphasize the importance of uptake and efflux transporters on hepatic drug metabolism.
在离体灌注大鼠肝脏中研究了地高辛的处置情况，以及有机阴离子转运多肽（Oatp）2抑制剂利福平、P-糖蛋白（P-gp）抑制剂奎尼丁对其肝脏处置的影响。给大鼠组静脉注射一剂地高辛（10微克）后，以循环方式灌注肝脏，地高辛是Oatp2、P-gp以及CYP3A的双重底物。还在存在抑制剂（利福平100微摩尔或奎尼丁10微摩尔）的大鼠组中研究了地高辛的灌注情况。在所有实验中，收集灌注液样本60分钟。通过液相色谱/质谱法测定灌注液和肝脏中的地高辛及其主要代谢产物。测定0至60分钟的曲线下面积（AUC）。地高辛的AUC±标准差从对照组（3880±210纳摩尔·分钟）因利福平而增加（5200±240纳摩尔·分钟；p<0.01），因奎尼丁而降低（3220±340纳摩尔·分钟；P<0.05）。得出的结论是，利福平通过抑制基底外侧Oatp2摄取转运限制了地高辛的肝脏摄取，并降低了地高辛对CYP3A的肝脏暴露，而奎尼丁通过抑制胆小管P-gp转运增加了地高辛对CYP3A的肝脏暴露。这些数据强调了摄取和外排转运体对肝脏药物代谢的重要性。
