19 Therefore, amoxicillin/clavulanate’s rechallenge injury is primarily immunoallergic. click here In a retrospective series, azathioprine-positive rechallenge was associated with hepatocellular injury in 71% of patients, jaundice in 43% of patients, and hypersensitivity in 14% of patients (n = 14).2 Whereas the initial liver injury occurred following 3 months of treatment, liver injury

with positive rechallenge was observed after only 10 days.2 The key mechanisms of azathioprine liver injury include hypersensitivity,2 glutathione depletion, oxidative stress with resultant mitochondrial impairment, and depletion of mitochondrial glutathione,42 ATP, and lipid peroxidation.43 Positive rechallenge events with nucleoside reverse-transcriptase

inhibitors selleck chemical generally resulted in asymptomatic hepatocellular injury in a retrospective series.2 Graded liver chemistry elevations were similar in severity in most patients undergoing rechallenge in comparison with the initial liver injury.2 The mechanisms involved in nucleoside reverse-transcriptase inhibitor-associated hepatotoxicity include the formation of a stavudine epoxide intermediate reactive metabolite44 and progressive mitochondrial impairment resulting from depletion of mitochondrial DNA. Among nucleoside reverse-transcriptase inhibitors, the rates of hepatotoxicity are highest in those drugs most potently inhibiting mitochondrial DNA synthesis in vitro: zalcitabine-didanosine, stavudine, and zidovudine-lamivudine.45

Therefore, mitochondrial impairment medchemexpress is a key mechanism of rechallenge injury, with a possible contribution from reactive metabolites. Drug-specific mechanisms of liver injury appear to influence the incidence, severity, and temporal onset of positive rechallenge events. Mitochondrial impairment and immunoallergic injury are associated with the highest rate of positive rechallenge (ranging from 11% to 51%) and fatality. Rechallenge within 1 month of halothane-induced jaundice results in a mortality rate of nearly 50%.3 However, for other drugs, rechallenge mortality rates range from 2% to 13%, and the severity of the primary liver injury does not clearly affect the severity of the rechallenge injury.2, 4 Hepatocellular injury and high daily drug dose (>50 mg) are also commonly observed in positive rechallenge. Drug rechallenge is generally avoided due to associated severe liver injury and fatalities.1, 2, 4 However, because drug rechallenge may be considered for life-saving therapies (e.g., oncology), evaluation of the mechanisms of liver injury may elucidate a drug’s potential for serious or fatal injury. Mitochondria supply most of a hepatocyte’s ATP and are thus central to hepatocyte survival.