Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone.

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 (IC(50) = 9 microM), inhibition of taurocholate efflux in human hepatocytes (IC(50) = 14 microM), and a transient increase in rat serum bile acids 1 h after oral drug administration.

Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes.

Here we present a preclinical model to assess drug-drug interactions due to inhibition of glucuronidation. Treatment with the antiepileptics phenobarbital (PB) or phenytoin (PH) has been associated with increased incidence of acetaminophen (APAP) hepatotoxicity in patients. In human hepatocytes, we found that the toxicity of APAP (5 mM) was increased by simultaneous treatment with phenobarbital (2 mM) or phenytoin (0.

Evaluation of hepatotoxic potential of drugs by inhibition of bile-acid transport in cultured primary human hepatocytes and intact rats.

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 min of addition to cells.