Yoon Insoo, Han Seungyon, Choi Young-Hee, Kang Hee-Eun, Cho Hyun-Jong, Kim Jung Sun, Shim Chang-Koo, Chung Suk-Jae, Chong Saeho, Kim Dae-Duk
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Xenobiotica. 2012 Nov;42(11):1110-9. doi: 10.3109/00498254.2012.700139. Epub 2012 Jul 2.
Identifying kinetic determinants of hepatic elimination of drugs would be crucial for better understanding its pharmacokinetics and predicting drug interactions. Present study investigated the kinetics of sinusoidal uptake of docetaxel and its impact on the overall hepatic elimination of docetaxel in rats. The non-renal clearance (CL(NR); hepatic elimination) of docetaxel were significantly reduced by co-administration of intravenous rifampicin, a potent inhibitor of organic anion transporting peptides (OATPs; Oatps), at a dose of 20 mg/kg. Docetaxel uptake into isolated rat hepatocytes was found to be temperature/concentration/energy-dependent, saturable, and reduced by Oatps inhibitors (rifampicin and bromosulfophthalein). Moreover, docetaxel uptake into perfused rat liver was significantly reduced in the presence of 10-µM rifampicin. However, docetaxel metabolism in rat hepatic microsome was not affected by rifampicin at less than 50 µM. Based on the comparison of intrinsic clearances related to hepatic clearance, it can be suggested that sinusoidal uptake could be the rate-determining process in the overall hepatic elimination of docetaxel in rats.
确定药物肝脏消除的动力学决定因素对于更好地理解其药代动力学和预测药物相互作用至关重要。本研究调查了多西他赛的肝血窦摄取动力学及其对大鼠多西他赛整体肝脏消除的影响。静脉注射利福平（一种有机阴离子转运肽（OATPs；Oatps）的强效抑制剂），剂量为20 mg/kg，可显著降低多西他赛的非肾清除率（CL(NR)；肝脏消除）。发现多西他赛进入分离的大鼠肝细胞的摄取是温度/浓度/能量依赖性的、可饱和的，并且会被Oatps抑制剂（利福平和溴磺酞）降低。此外，在存在10 μM利福平的情况下，多西他赛进入灌注大鼠肝脏的摄取显著降低。然而，在浓度低于50 μM时，利福平不会影响大鼠肝微粒体中的多西他赛代谢。基于与肝脏清除相关的内在清除率的比较，可以认为肝血窦摄取可能是大鼠多西他赛整体肝脏消除中的速率决定过程。
