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ToxSci Advance Access published online on August 27, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg217
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received July 2, 2003; accepted August 6, 2003
© 2003 Society of Toxicology

Risk Assessment

Evaluation of Hepatotoxic Potential of Drugs by Inhibition of Bile Acid Transport in Cultured Primary Human Hepatocytes and Intact Rats

Vsevolod E. Kostrubsky 1*, Stephen C. Strom 2, Janean Hanson 1, Ellen Urda 1, Kelly Rose 3, James Burliegh 3, Philip Zocharski 4, Hongbo Cai 2, Jacqueline F. Sinclair 5, and Jasminder Sahi 3

1 Department of Drug Safety Evaluation, Pfizer Global Research and Development, Ann Arbor, Michigan
2 University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania
3 Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor, Michigan
4 Department of Pharmaceutical Sciences, Pfizer Global Research and Development, Ann Arbor, Michigan
5 Veterans Administration Medical Center, White River Junction, Vermont; Departments of Biochemistry and Pharmacology/Toxicology, Dartmouth Medical School, Hanover, New Hampshire

* To whom correspondence should be addressed. E-mail: vsevolod.kostrubsky{at}pfizer.com.


  Abstract

Inhibition of canalicular bile acid efflux by medications is associated with clinical liver toxicity, sometimes in the absence of major liver effects in experimental species. To predict the hepatotoxic potential of compounds in vitro and in vivo, we investigated the effect of clinical cholestatic agents on [3H]taurocholic acid transport in regular and collagen-sandwich cultured human hepatocytes. Hepatocytes established a well-developed canalicular network with bile acid accumulating in the canalicular lumen within 15 minutes of addition to cells. Canalicular junctions were destroyed by removing Ca2+ and Mg2+ from the incubation buffer, resulting in bile acid efflux into the incubation buffer. Canalicular transport was calculated based on the difference between the amount of bile acid effluxed into the Ca/Mg2+-free and regular buffers with linear efflux up to 10 minutes. Hepatocytes cultured in the non-sandwich configuration also transported taurocholic acid, but at 50% the rate in sandwiched cultures. Cyclosporin A, bosentan, CI-1034, glyburide, erythromycin estolate and troleandomycin inhibited efflux in a concentration-dependent manner. In contrast, new generation macrolide antibiotics, with lower incidence of clinical hepatotoxicity, were much less potent inhibitors of efflux. An in vivo study was conducted, whereby glyburide or CI-1034 administered iv to male rats, produced a 2.4-fold increase in rat total serum bile acids. A synergistic 6.8-fold increase in serum total bile acids was found when both drugs were delivered together. These results provide methods to evaluate inhibitory effects of potentially cholestatic compounds on bile acid transport, and to rank compounds according to their hepatotoxic potential.

Key Words: cholestasis, preclinical, clinical, toxicity, hepatocytes, bile acids, microlides, transport .


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