Journal Article

Role of Hepatic Transporters in the Disposition and Hepatotoxicity of a HER2 Tyrosine Kinase Inhibitor CP-724,714

Bo Feng, Jinghai J. Xu, Yi-An Bi, Rouchelle Mireles, Ralph Davidson, David B. Duignan, Scott Campbell, Vsevolod E. Kostrubsky, Margaret C. Dunn, Arthur R. Smith and Huifen F. Wang

in Toxicological Sciences

Volume 108, issue 2, pages 492-500
Published in print April 2009 | ISSN: 1096-6080
Published online February 2009 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp033
Role of Hepatic Transporters in the Disposition and Hepatotoxicity of a HER2 Tyrosine Kinase Inhibitor CP-724,714

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CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clinical development due to unexpected hepatotoxicity in cancer patients. Based on the clinical manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition of CP-724,714, and its inhibition of active canalicular transport of bile constituents were evaluated in established human hepatocyte models and in vitro transporter systems. CP-724,714 exhibited direct cytotoxicity using human hepatocyte imaging assay technology with mitochondria identified as a candidate organelle for its off-target toxicity. Additionally, CP-724,714 was rapidly taken up into human hepatocytes, partially via an active transport process, with an uptake clearance approximately fourfold higher than efflux clearance. The major human hepatic uptake transporter, OATP1B1, and efflux transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein, were involved in hepatobiliary clearance of CP-724,714. Furthermore, CP-724,714 displayed a concentration-dependent inhibition of cholyl-lysyl fluorescein and taurocholate (TC) efflux into canaliculi in cryopreserved and fresh cultured human hepatocytes, respectively. Likewise, CP-724,714 inhibited TC transport in membrane vesicles expressing human bile salt export pump with an IC50 of 16μM. Finally, CP-724,714 inhibited the major efflux transporter in bile canaliculi, MDR1, with an IC50 of ∼28μM. These results suggest that inhibition of hepatic efflux transporters contributed to hepatic accumulation of drug and bile constituents leading to hepatocellular injury and hepatobiliary cholestasis. This study provides likely explanations for clinically observed adverse liver effects of CP-724,714.

Keywords: CP-724,714; hepatocytes; hepatic transporters; hepatotoxicity; mechanism

Journal Article.  5682 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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