Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites.
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Swift B, Nebot N, Lee JK, Han T, Proctor WR, Thakker DR, Lang D, Radtke M, Gnoth MJ, Brouwer KL
Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites.
Drug Metab Dispos. 2013 Jun;41(6):1179-86. doi: 10.1124/dmd.112.048181. Epub 2013 Mar 12.
- PubMed ID
- 23482500 [ View in PubMed]
- Abstract
Sorafenib is an orally active tyrosine kinase inhibitor used in the treatment of renal and hepatocellular carcinoma. This study was designed to establish whether transport proteins are involved in the hepatic uptake of sorafenib and to determine the extent of biliary excretion of sorafenib and its metabolites in human hepatocytes. Initial uptake was assessed in freshly isolated, suspended human hepatocytes in the presence of inhibitors and modulators. [(14)C]Sorafenib (1 microM) uptake at 4 degrees C was reduced by about 61-63% of the uptake at 37 degrees C, suggesting a high degree of passive diffusion. Hepatocyte uptake of [(14)C]sorafenib was not Na(+) dependent or influenced by the organic anion transporter 2 inhibitor ketoprofen. However, initial [(14)C]sorafenib hepatocyte uptake was reduced by 46 and 30% compared with control values in the presence of the organic anion transporting polypeptide inhibitor rifamycin SV and the organic cation transporter (OCT) inhibitor decynium 22, respectively. [(14)C]Sorafenib (0.5-5 microM) uptake was significantly higher in hOCT1-transfected Chinese hamster ovary cells compared with mock cells, and inhibited by the general OCT inhibitor, 1-methyl-4-phenylpryidinium. OCT1-mediated uptake was saturable with a Michaelis-Menten constant of 3.80 +/- 2.53 microM and a V(max) of 116 +/- 42 pmol/mg/min. The biliary excretion index and in vitro biliary clearance of sorafenib (1 microM) in sandwich-cultured human hepatocytes were low ( approximately 11% and 11 ml/min/kg, respectively). Results suggest that sorafenib uptake in human hepatocytes occurs via passive diffusion, by OCT1, and by organic anion transporting polypeptide(s). Sorafenib undergoes modest biliary excretion, predominantly as a glucuronide conjugate(s).
