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ToxSci Advance Access originally published online on January 12, 2006
Toxicological Sciences 2006 90(2):451-459; doi:10.1093/toxsci/kfj095
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inhibition of Hepatobiliary Transport as a Predictive Method for Clinical Hepatotoxicity of Nefazodone

Seva E. Kostrubsky*,1, Stephen C. Strom{dagger}, Amit S. Kalgutkar{ddagger}, Shaila Kulkarni*, James Atherton§, Rouchelle Mireles{ddagger}, Bo Feng{ddagger}, Raylene Kubik*, Janean Hanson*, Ellen Urda* and Abdul E. Mutlib§

* Departments of Safety Science and § Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor, Michigan 48105 and {ddagger} Groton, Connecticut 06340; and the {dagger} Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261

Received September 29, 2005; accepted January 9, 2006

Treatment with the antidepressant nefazodone has been associated with clinical idiosyncratic hepatotoxicty. Using membranes expressing human bile salt export pump (BSEP), human sandwich hepatocytes, and intact rats, we compared nefazodone and its marketed analogs, buspirone and trazodone. We found that nefazodone caused a strong inhibition of BSEP (IC50 = 9 µM), inhibition of taurocholate efflux in human hepatocytes (IC50 = 14 µM), and a transient increase in rat serum bile acids 1 h after oral drug administration. Buspirone or trazodone had no effect on biliary transport system. Nefazodone produced time- and concentration-dependent toxicity in human hepatocytes with IC50 = 18 µM and 30 µM measured by inhibition of protein synthesis after 6 h and 24 h incubation, respectively. Toxicity was correlated with the amount of unmetabolized nefazodone. Partial recovery in toxicity by 24 h has been associated with metabolism of nefazodone to sulfate and glucuronide conjugates. The saturation of nefazodone metabolism resulted in sustained decrease in protein synthesis and cell death at 50 µM. The toxicity was not observed with buspirone or trazodone. Addition of 1-aminobenzotriazole (ABT), an inhibitor of CYP450, resulted in enhancement of nefazodone toxicity at 10 µM and was associated with accumulation of unmetabolized nefazodone. In human liver microsomes, ABT also prevented metabolism of nefazodone and formation of glutathione conjugates. We suggest that inhibition of bile acid transport by nefazodone is an indicator of potential hepatotoxicity. Our findings are consistent with the clinical experience and suggest that described methodology can be applied in the selection of nonhepatotoxic drug candidates.

Key Words: BSEP; buspirone; trazodone; hepatocytes; metabolism.


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