REDUCTIVE HALOTHANE METABOLITE FORMATION AND HALOTHANE BINDING IN RAT HEPATIC MICROSOMES

The production of the reductive [14C]halothane metabolites, 2-chloro-1,1,1-trifluoroethane (CTE) and 2-chloro-1,1-difluoroethylene (CDE), was determined in anaerobic microsomal incubations by high pressure liquid chromatography (HPLC). The HPLC technique used allowed accurate measurements of low levels of [14C]halothane metabolites. Comparisons of metabolic profiles and halothane binding in microsomes reduced with NADPH and sodium dithionite show that dithionite stimulates CDE production and total halothane degradation, but inhibits CTE formation and [14C]-halothane binding. Similarly, the addition of isoflurane, but not enflurane, to microsomes increases CDE production and decreases CTE formation and [14C]halothane-lipid binding. Measurement of fluoride in similar incubations shows that fluoride release from halothane correlates with the formation of CDE and not CTE. The relative production of CTE and CDE may not remain constant in microsomal preparations; halothane binding appears to correlate CTE formation and not CDE and fluoride production. [Implications with respect to the hepatotoxicity of this drug and its metabolites are presented.].