Concentration-dependent inhibition of halothane biotransformation in the guinea pig
R. C. Lind, A. J. Gandolfi
Toxicology, Center for
BIO5, Institute of
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.
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Halothane Chemical Compounds 100%
Biotransformation Medicine & Life Sciences 82%
Guinea Pigs Medicine & Life Sciences 61%
Trifluoroacetic Acid Medicine & Life Sciences 40%
Anaesthetic Chemical Compounds 17%
Plasma Chemical Compounds 12%
Anesthetics Medicine & Life Sciences 11%
Refrigerant Chemical Compounds 9%
Lind, R. C., & Gandolfi, A. J. (1993). Concentration-dependent inhibition of halothane biotransformation in the guinea pig. Drug Metabolism and Disposition, 21(2), 386-389.
Concentration-dependent inhibition of halothane biotransformation in the guinea pig. / Lind, R. C.; Gandolfi, A. J.
In: Drug Metabolism and Disposition, Vol. 21, No. 2, 1993, p. 386-389.
Lind, RC & Gandolfi, AJ 1993, 'Concentration-dependent inhibition of halothane biotransformation in the guinea pig', Drug Metabolism and Disposition, vol. 21, no. 2, pp. 386-389.
Lind RC, Gandolfi AJ. Concentration-dependent inhibition of halothane biotransformation in the guinea pig. Drug Metabolism and Disposition. 1993;21(2):386-389.
Lind, R. C. ; Gandolfi, A. J. / Concentration-dependent inhibition of halothane biotransformation in the guinea pig. In: Drug Metabolism and Disposition. 1993 ; Vol. 21, No. 2. pp. 386-389.
@article{e327349997fa427592366eab0109d550,
title = "Concentration-dependent inhibition of halothane biotransformation in the guinea pig",
abstract = "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.",
author = "Lind, {R. C.} and Gandolfi, {A. J.}",
journal = "Drug Metabolism and Disposition",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
T1 - Concentration-dependent inhibition of halothane biotransformation in the guinea pig
AU - Lind, R. C.
AU - Gandolfi, A. J.
N2 - 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.
AB - 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.
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition