Concentration-dependent inhibition of halothane biotransformation in the guinea pig.
Previous studies have indicated concentration-dependent inhibition of halothane's biotransformation by the hepatic cytochrome P-450 enzyme system. In order to investigate this phenomenon in the guinea pig model of acute halothane-associated hepatotoxicity, male outbred Hartley guinea pigs underwent 4 hr inhalation exposures to either subanesthetic (0.1%) or anesthetic (1.0%) concentrations of halothane with 40% O2. Plasma concentrations of the primary halothane metabolite, trifluoroacetic acid (TFA) were one-half as great immediately (0 hr) after the 1% exposure as they were with 0.1%. By 10 hr after exposure plasma TFA had increased significantly in both treatment groups. However, there was a much greater rate of increase with 1% halothane so that values were now more than 50% greater than with 0.1% halothane. Plasma TFA in the 1% halothane group remained significantly greater over the 96-hr time course of the experiment. Covalent binding of reactive halothane biotransformation intermediates to hepatic protein paralleled plasma TFA. At 0 hr, the degree of binding in the 1% halothane group was one-half as great as in the 0.1% group and by 10 hr after had increased to be nearly twice as great as the 0.1% group that had not increased between the time points. These data provide strong evidence for substrate-specific inhibition of halothane biotransformation with the majority of biotransformation occurring in the hours following exposure to an anesthetic (1%) concentration of the drug. These metabolic dynamics should be considered in studies of other organohalogens, including the new refrigerants that are structurally similar to halothane.
Lind
R C
RC
Department of Anesthesiology, College of Medicine, University of Arizona, Tucson 85724.
Gandolfi
A J
AJ
D000758:Anesthesia; D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology; D006168:Guinea Pigs; D006221:Halothane / Q000493:pharmacokinetics* / Q000633:toxicity; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D011506:Proteins / Q000378:metabolism; D014269:Trifluoroacetic Acid / Q000097:blood
D011506:Proteins; D014269:Trifluoroacetic Acid; D006221:Halothane