Abstract

The in vivo metabolic rate constants for the metabolism of the chlorofluorocarbon replacement 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) were determined for both male and female rats with a physiologically based pharmacokinetic model. Uptake studies with 500-5,000 ppm HCFC-123 indicated that a single saturable component was involved in both sexes, and no significant differences were observed in in vivo metabolic rate constants between male and female rats. The in vivo metabolic rate constants obtained from computer simulation studies were: for male rats--KM = 1.2 mg liter-1 (7.85 mumol liter-1) and Vmaxc = 7.20 +/- 0.28 mg kg-1 hr-1 (47.1 +/- 1.83 mumol kg-1 hr-1); for female rats--KM = 1.2 mg liter-1 (7.85 mumol liter-1) and Vmaxc = 7.97 +/- 0.30 mg kg-1 hr-1 (52.1 +/- 1.96 mumol kg-1 hr-1). The physiologically based pharmacokinetic model failed to simulate the reduction in HCFC-123 uptake in female rats at 2,000-5,000 ppm. The production and excretion of trifluoroacetic acid, the major urinary metabolite of HCFC-123, was also predicted by the physiologically based pharmacokinetic model with in vivo metabolic rate constants obtained in the gas-uptake simulation studies. Diallyl sulfide, a selective, mechanism-based inhibitor of cytochrome P450 2E1, inhibited the metabolism of HCFC-123, as indicated by a decreased uptake of HCFC-123 and by a lowered urinary excretion of trifluoroacetic acid in diallyl sulfide-treated rats.