Loizou G D, Urban G, Dekant W, Anders M W
Department of Pharmacology, University of Rochester, NY 14642.
Drug Metab Dispos. 1994 Jul-Aug;22(4):511-7.
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.
利用基于生理学的药代动力学模型，测定了雄性和雌性大鼠体内氯氟烃替代物2,2 - 二氯 - 1,1,1 - 三氟乙烷（HCFC - 123）代谢的代谢速率常数。对500 - 5000 ppm HCFC - 123的摄取研究表明，两性均涉及单一的可饱和成分，并且雄性和雌性大鼠体内的代谢速率常数未观察到显著差异。通过计算机模拟研究获得的体内代谢速率常数为：雄性大鼠——KM = 1.2毫克/升（7.85微摩尔/升），Vmaxc = 7.20±0.28毫克/千克·小时-1（47.1±1.83微摩尔/千克·小时-1）；雌性大鼠——KM = 1.2毫克/升（7.85微摩尔/升），Vmaxc = 7.97±0.30毫克/千克·小时-1（52.1±1.96微摩尔/千克·小时-1）。基于生理学的药代动力学模型未能模拟雌性大鼠在2000 - 5000 ppm时HCFC - 123摄取的减少。基于生理学的药代动力学模型还利用在气体摄取模拟研究中获得的体内代谢速率常数预测了HCFC - 123的主要尿代谢产物三氟乙酸的产生和排泄。二烯丙基硫醚是细胞色素P450 2E1的一种选择性、基于机制的抑制剂，它抑制了HCFC - 123的代谢，这表现为在二烯丙基硫醚处理的大鼠中HCFC - 123摄取减少以及三氟乙酸的尿排泄降低。
