Abstract
Difluoromethoxydifluoroacetic acid (CHF2OCF2CO2H) has been identified as a metabolite of enflurane (CHF2OCF2CHCIF) in rat liver microsomes in vitro and in human urine by gas chromatography mass spectrometry. The formation of the metabolite in rat liver microsomes was dependent upon the presence of NADPH and O2, and was inhibited when SKF 525-A or CO/O2 (8:2, v/v) were present in the reaction mixture. When the C-H bonds of the CHCIF group of enflurane or of the CHCI group of isoflurane (CHF2OCHCICF3) were replaced with a C-CI bond, virtually no fluoride ion was produced from either derivative in rat liver microsomes. These results indicate that cytochrome P-450 catalyzes the oxidative dehalogenation of CHF2OCF2CHCIF at its CHCIF group to form CHF2OCF2CO2H and chloride and fluoride ions. In contrast, the CHF2 group does not appear to be appreciably susceptible to metabolic oxidative dehalogenation. These results can be used for the more rational design of new inhalation anesthetics that would not be appreciably metabolized to the potential kidney toxin, F-.
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
