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Xenobiotica
the fate of foreign compounds in biological systems
Volume 42, 2012 - Issue 11
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Animal Pharmacokinetics and Metabolism

Saturable sinusoidal uptake is rate-determining process in hepatic elimination of docetaxel in rats

, , , , , , , , & show all
Pages 1110-1119 | Received 31 Mar 2012, Accepted 31 May 2012, Published online: 02 Jul 2012
 

Abstract

  1. 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.

  2. The non-renal clearance (CLNR; 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.

  3. 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.

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