Factors affecting the formation of chlorotrifluoroethane and chlorodifluoroethylene from halothane

Since CF₃CH₂Cl and CF₂CHCl are probably the products of reactive intermediates formed during the reductive metabolism of halothane (CF₃CHClBr), factors affecting their in vitro and in vivo formation were investigated. In vitro studies with rat hepatic microsomes showed that CF₃CH₂Cl and CF₂CHCl are produced by cytochrome P-450 mediated reductive pathways which were inhibited by the presence of CO. Under conditions of exposure known to promote halothane hepatotoxicity in phenobarbital treated rats (1% halothane, 14% oxygen), the hepatic and blood concentrations of the volatile metabolites were enhanced. Central venous levels of the volatile metabolites were much higher than the concentration in peripheral vessels. The CF₃CH₂Cl/CF₂CHCl ratio in blood was approximately three, whereas the ratio in vitro was almost unity. Liver levels of the two volatile metabolites greatly exceeded the blood levels, but interestingly they were present in equivalent concentrations. The differences in the ratio of CF₃CH₂Cl to CF₂CHCl may be explained by the fact that CF₂CHCl is further degraded under oxidative conditions, whereas CF₃CH₂Cl appears relatively stable. Measurement of these metabolic products in patients undergoing halothane anesthesia may permit rapid detection of an unusually high level of halothane biotransformation along its hepatotoxic pathway.