Br.J. Anaesth. (1975), 47, 1157
SPECIES, STRAIN, SEX AND INDIVIDUAL DIFFERENCES IN ENFLURANE METABOLISM B. A. HITT, R. I. MAZZE, W. C. STEVENS, A. WHITE AND E. I. EGER II SUMMARY
Variation in drug metabolism among different species METHODS and strains is well known (Jay, 1955; Quinn, Axelrod Species differences and Brodie, 1958; Davies, Gigonand Gillette, 1969; Six male and six female adult ICR mice, eight male Kato, Onoda and Takanaka, 1970). Also, it has been and eight female adult Hartley guineapigs and eight established that differences exist among individuals male and eight female adult Sprague-Dawley rats within a given strain and that consistent differences were placed in one side of a two-compartment in metabolism between sexes occur only in rats (Jay, environmental chamber. Each compartment was 5 ft 1955; Kato, Onoda and Takanaka, 1970; El Defrawy, high, 3 ft wide and 3 ft deep. Animals breathed 0.2% Cohen and Mannering, 1974). These differences exist enflurane (range 0.19-0.21%; 0.1 MAC) for 35 days. across the entire spectrum of metabolic variables: Three male and three female mice, eight male and pathways, rates, amounts and metabolism. Variations seven female guineapigs and six male and six female in pathways can result from genetic differences in Sprague-Dawley rats (control group) were placed in enzyme structure while variations in the rate of the other compartment and were not exposed to metabolism may occur either because of quantitative enflurane vapour. Gases from both chambers were or qualitative enzyme differences or as a result of sampled automatically every 8 hr and the anaesthetic differences in pharmacokinetic properties of the sub- concentration was determined by gas chromatography. strate, such as tissue distribution and protein binding After the 35th day of exposure, the animals were (Williams, 1971). We have reported differences in the sacrificed by decapitation. Blood was collected from rate of methoxyflurane metabolism among five rat each animal, allowed to clot, centrifuged, and the strains following exposure to anaesthetic concentra- serum decanted and frozen at —15 °C for subsequent tions of that drug (Mazze, Cousins and Kosek, 1973). analysis. Specimens were analysed for the inorganic This study employs continuous exposure of mice, fluoride concentration with an Orion ion specific guineapigs and rats to subanaesthetic concentrations electrode (Fry and Taves, 1970) and for urea nitrogen of enflurane to examine, further, differences in with an automated method (Marsh, Fingerhut and defluorination of inhalation anaesthetic agents and Miller, 1965). to determine whether strain differences in the pattern In a second experiment, six male and six female of enzyme induction occur with enflurane. guineapigs and eight male and eight female SpragueDawley rats were treated as above except that they BEN A. Hrrr, PH.D.; RICHARD I. MAZZE, M.D.; Departments breathed 0.07% enflurane for 35 days. The serum of Anesthesia, Stanford University School of Medicine, Stanford, California 94305, and Veterans Administration was analysed for inorganic fluoride activity. Hospital, Palo Alto, California 94304, U.S.A.; WENDELL C. STEVENS, M.D.; ANNE WHITE, M.D.; EDMOND I. EGER, II,
M.D.; Department of Anesthesia, University of California Medical Center, S.F., San Francisco, California 94143, U.S.A.
Strain differences and enzyme induction Groups of 16 male Sprague-Dawley and 16 male Fischer 344 rats, bedded on paper cage liners for
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 15, 2015
Species, sex and individual differences in serum inorganic fluoride concentrations were demonstrated in mice, guineapigs and rats exposed to either 0.07% or 0.2% enflurane for 35 days, suggesting differences in enflurane biotransformation. Exposure of Fischer 344 rats and Sprague-Dawley.rats to 0.2% enflurane for 8 days resulted in enzyme induction as demonstrated by increasing serum inorganic fluoride and cytochrome P-450 concentrations. However, there was no difference in cytochrome P-450 concentrations between the strains despite differences in inorganic fluoride concentration. These results emphasize the multiplicity of factors and the lack of predictability in patterns of enflurane metabolism among species, strains and individuals.
BRITISH JOURNAL OF ANAESTHESIA
1158
Statistical methods The mean and SEM of each variable for each group were calculated and the values were compared using Student's t test. Where P
SPECIES, STRAIN, SEX AND INDIVIDUAL DIFFERENCES IN ENFLURANE METABOLISM B. A. HITT, R. I. MAZZE, W. C. STEVENS, A. WHITE AND E. I. EGER II SUMMARY
Variation in drug metabolism among different species METHODS and strains is well known (Jay, 1955; Quinn, Axelrod Species differences and Brodie, 1958; Davies, Gigonand Gillette, 1969; Six male and six female adult ICR mice, eight male Kato, Onoda and Takanaka, 1970). Also, it has been and eight female adult Hartley guineapigs and eight established that differences exist among individuals male and eight female adult Sprague-Dawley rats within a given strain and that consistent differences were placed in one side of a two-compartment in metabolism between sexes occur only in rats (Jay, environmental chamber. Each compartment was 5 ft 1955; Kato, Onoda and Takanaka, 1970; El Defrawy, high, 3 ft wide and 3 ft deep. Animals breathed 0.2% Cohen and Mannering, 1974). These differences exist enflurane (range 0.19-0.21%; 0.1 MAC) for 35 days. across the entire spectrum of metabolic variables: Three male and three female mice, eight male and pathways, rates, amounts and metabolism. Variations seven female guineapigs and six male and six female in pathways can result from genetic differences in Sprague-Dawley rats (control group) were placed in enzyme structure while variations in the rate of the other compartment and were not exposed to metabolism may occur either because of quantitative enflurane vapour. Gases from both chambers were or qualitative enzyme differences or as a result of sampled automatically every 8 hr and the anaesthetic differences in pharmacokinetic properties of the sub- concentration was determined by gas chromatography. strate, such as tissue distribution and protein binding After the 35th day of exposure, the animals were (Williams, 1971). We have reported differences in the sacrificed by decapitation. Blood was collected from rate of methoxyflurane metabolism among five rat each animal, allowed to clot, centrifuged, and the strains following exposure to anaesthetic concentra- serum decanted and frozen at —15 °C for subsequent tions of that drug (Mazze, Cousins and Kosek, 1973). analysis. Specimens were analysed for the inorganic This study employs continuous exposure of mice, fluoride concentration with an Orion ion specific guineapigs and rats to subanaesthetic concentrations electrode (Fry and Taves, 1970) and for urea nitrogen of enflurane to examine, further, differences in with an automated method (Marsh, Fingerhut and defluorination of inhalation anaesthetic agents and Miller, 1965). to determine whether strain differences in the pattern In a second experiment, six male and six female of enzyme induction occur with enflurane. guineapigs and eight male and eight female SpragueDawley rats were treated as above except that they BEN A. Hrrr, PH.D.; RICHARD I. MAZZE, M.D.; Departments breathed 0.07% enflurane for 35 days. The serum of Anesthesia, Stanford University School of Medicine, Stanford, California 94305, and Veterans Administration was analysed for inorganic fluoride activity. Hospital, Palo Alto, California 94304, U.S.A.; WENDELL C. STEVENS, M.D.; ANNE WHITE, M.D.; EDMOND I. EGER, II,
M.D.; Department of Anesthesia, University of California Medical Center, S.F., San Francisco, California 94143, U.S.A.
Strain differences and enzyme induction Groups of 16 male Sprague-Dawley and 16 male Fischer 344 rats, bedded on paper cage liners for
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 15, 2015
Species, sex and individual differences in serum inorganic fluoride concentrations were demonstrated in mice, guineapigs and rats exposed to either 0.07% or 0.2% enflurane for 35 days, suggesting differences in enflurane biotransformation. Exposure of Fischer 344 rats and Sprague-Dawley.rats to 0.2% enflurane for 8 days resulted in enzyme induction as demonstrated by increasing serum inorganic fluoride and cytochrome P-450 concentrations. However, there was no difference in cytochrome P-450 concentrations between the strains despite differences in inorganic fluoride concentration. These results emphasize the multiplicity of factors and the lack of predictability in patterns of enflurane metabolism among species, strains and individuals.
BRITISH JOURNAL OF ANAESTHESIA
1158
Statistical methods The mean and SEM of each variable for each group were calculated and the values were compared using Student's t test. Where P
