Gas-uptake pharmacokinetics and biotransformation of 1,1-dichloro-1-fluoroethane (HCFC-141b).
A physiologically based pharmacokinetic model was used to determine the in vivo metabolic constants of the candidate chlorofluorocarbon replacement 1,1-dichloro-1-fluoroethane (HCFC-141b). Rats were exposed by inhalation to HCFC-141b concentrations ranging from 1,000 to 10,000 ppm. Uptake studies of HCFC-141b in the rat indicated the involvement of saturable and first-order components. The in vivo metabolic constants for HCFC-141b were: KM = 7.0 mg liter-1 (59.9 mumol liter-1), Vmax = 0.2 mg kg-1 hr-1 (1.71 mumol kg-1 hr-1), and k = 0.5 hr-1. In rats exposed to HCFC-141b, 2,2-dichloro-2-fluoroethanol was excreted in the urine as its glucuronide conjugate, and the rate of 2,2-dichloro-2-fluoroethanol excretion increased linearly with increasing HCFC-141b exposure concentrations. Diallyl sulfide, a selective, mechanism-based inhibitor of cytochrome P-450 2E1, inhibited the metabolism of HCFC-141b, as indicated by a decreased uptake of HCFC-141b and by a lowered urinary excretion of 2,2-dichloro-2-fluoroethanol in diallyl-sulfide-treated rats. In vitro biotransformation studies with microsomes from rats treated with pyridine, an inducer of cytochrome P-450 2E1, confirmed that cytochrome P-450 2E1 is involved in the metabolism of HCFC-141b. The in vitro metabolic rate constants for the biotransformation of HCFC-141b to 2,2-dichloro-2-fluoroethanol were: KM = 0.39 +/- 0.11 mM and Vmax = 2.08 +/- 0.23 nmol mg protein-1 hr-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Loizou
G D
GD
Department of Pharmacology, University of Rochester, NY 14642.
Anders
M W
MW
D000498:Allyl Compounds; D000818:Animals; D001711:Biotransformation; D017402:Chlorofluorocarbons / Q000378:metabolism / Q000493:pharmacokinetics*; D064227:Chlorofluorocarbons, Ethane; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives / Q000652:urine; D005740:Gases; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013440:Sulfides / Q000494:pharmacology
D000498:Allyl Compounds; D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; D005740:Gases; D013440:Sulfides; C083193:2,2-dichloro-2-fluoroethanol; C038491:allyl sulfide; D005023:Ethylene Chlorohydrin; C068320:1,1-dichloro-1-fluoroethane