title: Acetaminophen predisposes to renal and hepatic injury from compound A in the fasting rat.
abstract: Results of previous studies of Compound A, a degradation product of sevoflurane, suggested that decreases in glutathione stores may increase potential Compound A nephrotoxicity. By depleting these stores, fasting and various drugs may augment such nephrotoxicity. To test this possibility, we pretreated 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.
authors.affiliation: Department of Anesthesia, University of California, San Francisco 94143-0464, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Laster
authors.forename: D
authors.initials: D
authors.lastname: Gong
authors.forename: R L
authors.initials: RL
authors.lastname: Kerschmann
authors.forename: E I
authors.initials: EI
authors.lastname: Eger
authors.forename: J L
authors.initials: JL
authors.lastname: Martin
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D004987:Ethers / Q000633:toxicity*; D005215:Fasting / Q000009:adverse effects*; D006845:Hydrocarbons, Fluorinated / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D018712:Analgesics, Non-Narcotic; D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D000082:Acetaminophen; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether