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

Insoo Yoon, Seungyon Han, Young Hee Choi, Hee Eun Kang, Hyun Jong Cho, Jung Sun Kim, Chang Koo Shim, Suk Jae Chung, Saeho Chong, Dae Duk Kim

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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 (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 20mg/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-M rifampicin. However, docetaxel metabolism in rat hepatic microsome was not affected by rifampicin at less than 50 M. 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.

Original languageEnglish
Pages (from-to)1110-1119
Number of pages10
JournalXenobiotica
Volume42
Issue number11
DOIs
StatePublished - Nov 2012

Keywords

  • Docetaxel
  • Hepatic elimination
  • Rats
  • Rifampicin
  • Sinusoidal uptake

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