Dose-dependent metabolism of 2,2-dichloro-1,1,1-trifluoroethane: a physiologically based pharmacokinetic model in the male Fischer 344 rat.
2,2-Dichloro-1,1,1-trifluorethane (HCFC-123) is used industrially as a refrigerant, as a foam blowing agent, and as a solvent. It is also being considered as a replacement for halons and chlorinated fluorocarbons which have been banned by the Montreal Protocol because they deplete atmospheric ozone. Male Fischer 344 rats were exposed to 1.0, 0.1, and 0.01% HCFC-123 by inhalation. Parent compound was measured in blood, fat, and exhaled breath and trifluoroacetic acid (TFA) was measured in blood and urine. A physiologically based pharmacokinetic (PBPK) model was developed which included a gut compartment and a variable size fat compartment in addition to the standard flow-limited compartments. Compartment volumes and flows were chosen from the literature, partition coefficients were measured in the laboratory, and metabolic parameters were optimized from experimental data using model simulations. Laboratory experiments showed that the TFA blood concentration during the 1.0% exposure was more than 50% less than the TFA blood concentration during the 0.1% exposure. After cessation of the 4-hr exposure, TFA blood concentrations from the 1.0% exposure rebounded and peaked between 12 and 26 hr after the exposure at about the same concentration as the 0.1% peak. This rebound phenomenon suggested that it was not killing of the metabolic enzymes but substrate inhibition that made the TFA blood concentrations lower than expected. Substrate inhibition by halothane, a structural analog of HCFC-123, has been described in the literature. Only by including a term for substrate inhibition in the PBPK model could pharmacokinetic data for TFA in blood be simulated adequately. This combination of laboratory experimentation and PBPK modeling can be applied to relate the levels of parent and metabolite to toxic effects with some hope of elucidating the toxic species. This work is the first step toward developing models that can be used to predict the toxicokinetics of HCFC-123 in humans throughout various potential use scenarios.
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ManTech Environmental Technology, Inc., Dayton, Ohio 45437.
Williams
R J
RJ
Fisher
J W
JW
McDougal
J N
JN
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000280:Administration, Inhalation; D000818:Animals; D001774:Blood Chemical Analysis; D001944:Breath Tests; D017402:Chlorofluorocarbons / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D064227:Chlorofluorocarbons, Ethane; D002849:Chromatography, Gas; D004305:Dose-Response Relationship, Drug; D005410:Flame Ionization; D008297:Male; D008954:Models, Biological; D008962:Models, Theoretical; D051381:Rats; D011916:Rats, Inbred F344; D014269:Trifluoroacetic Acid / Q000097:blood* / Q000652:urine
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; C067411:2,2-dichloro-1,1,1-trifluoroethane; D014269:Trifluoroacetic Acid