ACETAMINOPHEN PREDISPOSES TO RENAL AND HEPATIC-INJURY FROM COMPOUND-AIN THE FASTING RAT

Results of previous studies of Compound A, a degradation product of se voflurane, suggested that decreases in glutathione stores may increase potential Compound A nephrotoxicity. By depleting these stores, fasti ng and various drugs may augment such nephrotoxicity. To test this pos sibility, we pretreated fasted Fisher rats with intraperitoneal 0 (veh icle only), 250, 500, or 1000 mg/kg of acetaminophen, a commonly used drug that depletes glutathione stores. After pretreatment, we administ ered Compound A for 3 h at concentrations ranging from 0 to 200 ppm. T he larger doses of acetaminophen predisposed to greater renal and hepa tic injury. For example, at 100 ppm Compound A, no rats had renal cort ical injury when given vehicle only or 250 mg/kg acetaminophen, but 90 % (9 of 10 rats) had injury at 500 mg/kg and 100% (13 of 13) at 1000 m g/kg. Similarly, at 100 ppm Compound A, hepatic injury was not evident with vehicle only or 250 mg/kg, but occurred in 30% of rats at 500 mg /kg, and in 69% at 1000 mg/kg. Given the considerable differences betw een humans and rats, and given the large doses of acetaminophen requir ed, the clinical relevance of these findings is unclear. If clinically relevant, circumstances producing glutathione depletion (e.g., ingest ion of drugs such as acetaminophen, or nutritional deficiencies) may p redispose to renal or hepatic injury from Compound A in patients given sevoflurane at low fresh gas flow rates.