Drug-induced Liver Fibrosis: Testing Nevirapine in a Viral-like Liver Setting Using Histopathology, MALDI IMS, and Gene Expression.

Nevirapine (NVP) is associated with hepatotoxicity in 1-5% of patients. In rodent studies, NVP has been shown to cause hepatic enzyme induction, centrilobular hypertrophy, and skin rash in various rat strains but not liver toxicity. In an effort to understand whether NVP is metabolized differently in a transiently inflamed liver and whether a heightened immune response alters NVP-induced hepatic responses, female brown Norway rats were dosed with either vehicle or NVP alone (75 mg/kg/day for 15 days) or galactosamine alone (single intraperitoneal [ip] injection on day 7 to mimic viral hepatitis) or a combination of NVP (75/100/150 mg/kg/day for 15 days) and galactosamine (single 750 mg/kg ip on day 7). Livers were collected at necropsy for histopathology, matrix-assisted laser desorption/ionization imaging mass spectrometry and gene expression. Eight days after galactosamine, hepatic fibrosis was noted in rats dosed with the combination of NVP and galactosamine. No fibrosis occurred with NVP alone or galactosamine alone. Gene expression data suggested a viral-like response initiated by galactosamine via RNA sensors leading to apoptosis, toll-like receptor, and dendritic cell responses. These were exacerbated by NVP-induced growth factor, retinol, apoptosis, and periostin effects. This finding supports clinical reports warning against exacerbation of fibrosis by NVP in patients with hepatitis C.

Brief communication: intraperitoneal galactosamine misdosing as a possible interpretation for responder/nonresponder phenotypes.

Previous reports investigating the mechanisms of galactosamine toxicity have discussed the presence of responders and nonresponders after intraperitoneal (IP) administration of a toxic dose. The incidence of nonresponders has been reported to be as high as 47%. To rule out inadvertent intestinal, solid organ, or subcutaneous injection as at least a partial cause for the variability, we performed midline incisions and dosed 10 rats via a flexible catheter, with a toxic dose of galactosamine. Results were compared to a previous range finding study with IP-injected rats. As opposed to the IP-injected rats that had a roughly 50% response rate (based on serum alanine aminotransferase [ALT] elevation) and 100% of the midline incision catheter-instilled rats had elevations in ALT. Saline controls had no elevations. Histopathologic examination of livers from 5 midline-incisioned rats euthanized 48 hr after dosing with the lowest ALT responses revealed portal eosinophilic infiltrates and biliary hypertrophy/hyperplasia contiguous with areas of necrosis. Examination of 5 rats with the highest ALT elevations euthanized 10 days post dose revealed similar lesions to be resolving. We conclude that a significant contribution to variability in response to IP-injected galactosamine and possibly other investigative drugs is inadvertent misinjection of all or part of the dose.