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

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-1 (2.03 mumol litre-1) and Vmaxc = 9.2 mg kg1 h-1 (46.6 mumol kg1 h-1); for female rats, Km = 0.4 mg litre-1 (2.03 mumol litre-1) and Vmaxc = 10.2 mg kg-1 h-1 (51.7 mumol kg-1 h-1). 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 amount of enzyme 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.