Physiologically based pharmacokinetic analysis of the concentration- dependent metabolism of halothane

Abstract

1. Previous studies with the halothane analogue and chlorofluorocarbon replacement 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) have shown that there are concentration dependent, sex-specific differences in the rate of uptake during inhalation exposure in rat. Since it is well established that there are sex-specific differences in the control of enzyme activity in drug metabolism, male and female rats were exposed by inhalation to halothane concentrations ranging from 500 to 4000 ppm. 2. A physiologically based pharmacokinetic model describing the concentration dependent reduction in uptake and metabolism of halothane in male and female rats was developed. The in vivo metabolic rate constants obtained were : for male rats, Km 0 4 mg litre (2 03 mu mol litre) and Vmaxc 9 2 mg kg h (46 6 mu mol kg h); for female rats, Km 0 4 mg litre (2 03 mu mol litre) and Vmaxc 10 2 mg kg h (51 7 mu mol kg h) . 3. An equation describing the concentration-dependent decrease of hepatic metabolism of halothane successfully simulated the gas-uptake data. Simulation of cumulative urinary excretion of the major metabolite, trifluoroacetic acid, required introduction of a proportionality constant to limit the extent of reduction of halothane metabolism to 20% of the amountofenzyme activity. Good simulation of urinary excretion data was achieved, which was interpreted to indicate that, when only 20% of the enzyme is inactivated, the rate of enzyme resynthesis was adequate to replenish enzyme activity within 24 h. 4. A rapidly reversible, non-biological inactivation mechanism called 'physical toxicity' is discussed as a possible explanation of concentration-dependent gas uptake.