title: Saturable sinusoidal uptake is rate-determining process in hepatic elimination of docetaxel in rats.
abstract: 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.
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors: Insoo
authors: I
authors: Yoon
authors: Seungyon
authors: S
authors: Han
authors: Young-Hee
authors: YH
authors: Choi
authors: Hee-Eun
authors: HE
authors: Kang
authors: Hyun-Jong
authors: HJ
authors: Cho
authors: Jung Sun
authors: JS
authors: Kim
authors: Chang-Koo
authors: CK
authors: Shim
authors: Suk-Jae
authors: SJ
authors: Chung
authors: Saeho
authors: S
authors: Chong
authors: Dae-Duk
authors: DD
authors: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000077143:Docetaxel; D004791:Enzyme Inhibitors; D022781:Hepatocytes / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin; D043823:Taxoids / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D027361:Organic Anion Transporters; D043823:Taxoids; D000077143:Docetaxel; D012293:Rifampin