Cholestasis drug-induced hepatotoxicity

Fatal cholestatic hver failure occurred in a 45-year-old woman with metastatic breast cancer who was given gemcitabine and carboplatin and pre-existing liver damage. After four courses of gemcitabine -I- carboplatin she developed severe decompensated cholestatic hepatitis (9). Liver biopsy showed marked cholestasis and hepatocellular injury consistent with drug-induced hepatotoxicity. 

The best clinical evidence that BSEP is involved in hepatotoxicity is provided by human genetic studies which found four highly conserved non-synonymous mutations in two hepatobiliary transporters (BSEP and MDR3) that were specific for drug-induced liver injury [118]. Recently, a consortium of investigators identified a remarkable 82 different ABCBll mutations in 109 families that caused severe BSEP deficiency [119]. It is therefore expected that at least some of these genetic mutations and polymorphisms will put patients at an increased risk of drug-induced cholestasis. Does this justify the implementation of a simple BSEP inhibition screen for all new chemical entities The answer is not quite that simple. 

Rodrigues AD, Lai Y, Cvijic ME, EUdn LL, Zvyaga T, Soars MG (2014). Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity mechanistic considerations beyond the direct inhibition of the bile salt export pump. Drug Metab Dispos 42, 566-74. 

Liver There are a small number of reported cases of ajmaline-induced hepatitis or cholestasis associated witii chronic use of the drug. In all reports, patients had a similar clinical picture and recovered after conservative therapy. However, there are no other reports of hepatotoxicity occurring after the administration of low doses in diagnostic challenges. The mechanism of this side effect may be related to polymorphism of CYP 2D6 which is the main enzyme responsible for ajmaline metabolism. Routine liver function testing is recommended before an ajmaline challenge [10]. 

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