Effects of exposure concentrations on distribution of halothane metabolites in the body.
The effect of exposure concentration on halothane metabolism was studied in rats exposed to subanesthetic concentrations of halothane in air. Concentrations of halothane, total nonvolatile fluorine, and volatile metabolites (CF3CH2Cl and CF2 = CHCl) were determined in liver, kidneys, muscles, and brains excised at the end of a 3-hr exposure. It was observed that concentrations of all halothane metabolites in tissues rose less than exposure concentrations, that nonvolatile fluorine was present in all tissues in approximately the same concentrations, and that concentrations of volatile metabolites in liver were much higher than in any other tissues. A simulation model was used to support the following conclusions. Metabolism of halothane by all metabolic pathways is flow limited at small exposure concentrations and is capacity limited at high exposure concentrations. Volatile metabolites formed in livers are efficiently removed from circulation by pulmonary clearance, but trifluoroacetic acid is accumulated in the body. Halothane is most susceptible to biodegradation to trifluoroacetic acid, but this pathway is saturated at very small exposure concentrations. Susceptibility to biodegradation of volatile metabolites is small, but the pathways are not saturated even at anesthetic concentrations. The contribution of each of the three metabolites to total metabolic clearance depends on exposure concentrations. Trifluoroacetic acid was the major metabolite during exposure to small halothane concentrations; formation of more toxic, volatile metabolites increased during exposure to high concentrations. Postmortem formation of metabolites was studied in order to prevent its interference with tissue analysis. The method for determination of volatile metabolites is described.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006221:Halothane / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014269:Trifluoroacetic Acid / Q000378:metabolism
D014269:Trifluoroacetic Acid; D006221:Halothane