Influence of sevoflurane on the metabolism and renal effects of compound A in rats.
BACKGROUND
The sevoflurane degradation product compound A is nephrotoxic in rats. In contrast, patient exposure to compound A during sevoflurane anesthesia has no clinically significant renal effects. The mechanism for this difference is incompletely understood. One possibility is that the metabolism and toxicity of compound A in humans is prevented by sevoflurane. However, the effect of sevoflurane on compound A metabolism and nephrotoxicity is unknown. Thus, the purpose of this investigation was to determine the effect of sevoflurane on the metabolism and renal toxicity of compound A in rats.


METHODS
Male rats received 0.25 mmol/kg intraperitoneal compound A, alone and during sevoflurane anesthesia (3%, 1.3 minimum alveolar concentration, for 3 h). Compound A metabolites in urine were quantified, and renal function was evaluated by serum creatinine and urea nitrogen, urine volume, osmolality, protein excretion, and renal tubular histology.


RESULTS
Sevoflurane coadministration with compound A inhibited compound A defluorination while increasing relative metabolism through pathways of sulfoxidation and beta-lyase-catalyzed metabolism, which mediate toxicity. Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity.


CONCLUSIONS
Sevoflurane does not suppress compound A nephrotoxicity in rats in vivo. These results do not suggest that lack of nephrotoxicity in surgical patients exposed to compound A during sevoflurane anesthesia results from an inhibitory effect of sevoflurane on compound A metabolism and toxicity. Rather, these results are consistent with differences between rats and humans in compound A exposure and inherent susceptibility to compound A nephrotoxicity.
Kharasch
Evan D
ED
Department of Anesthesiology, University of Washington, Seattle, WA, USA. kharasch@wustl.edu
Schroeder
Jesara L
JL
Sheffels
Pam
P
Liggitt
H Denny
HD
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation; D004987:Ethers / Q000378:metabolism* / Q000633:toxicity* / Q000652:urine; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism* / Q000633:toxicity* / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D000077149:Sevoflurane; D013454:Sulfoxides / Q000378:metabolism
D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D013454:Sulfoxides; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether