Acetaminophen Predisposes to Renal and Hepatic Injury from Compound A in the Fasting Rat

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Abstract
Eated fasted Fisher rats with intraperitoneal 0 (vehicle only), 250, 500, or 1000 mg/kg of acetaminophen, a commonly used drug that depletes glutathione stores. After pretreatment, we administered Compound A for 3 h at concentrations ranging from 0 to 200 ppm. The larger doses of acetaminophen predisposed to greater renal and hepatic injury. For example, at 100 ppm Compound A, no rats had renal cortical 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 mg/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 between humans and rats, and given the large doses of acetaminophen required, the clinical relevance of these findings is unclear. If clinically relevant, circumstances producing glutathione depletion (e.g., ingestion of drugs such as acetaminophen, or nutritional deficiencies) may predispose to renal or hepatic injury from Compound A in patients given sevoflurane at low fresh gas flow rates. (Anesth Analg 1997;84:169-72)...