Trideuteromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether was synthesized by the reductive dechlorination of trichloromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether. This reaction was performed by zinc/zinc chloride catalyzed reduction in acetic acid-D. This reaction yielded 80% methyl 1,1,1,3,3,3-hexafluoroisopropyl ether consisting of approximately 70% trideuteromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether and 26% dideuteromethyl 1,1,1,3,3,3-hexafluoro-isopropyl ether.

Isoflurane stimulates the metabolism of 2-chloro-1,1-difluoroethene (CDE) in liver microsomes from phenobarbital-treated rats or rabbits. The P450 isozymes involved and the mechanism by which such stimulation occurs have not been clarified. The present study examined the effects of isoflurane and cytochrome b5 on CDE metabolism in reconstituted systems containing purified rat CYP2B1 or CYP2C6. Under similar incubation conditions, CYP2B1 defluorinated CDE at approximately five times the rate of CYP2C6. Isoflurane was a potent stimulator of CDE metabolism, increasing it nearly 5-fold when catalyzed by CYP2B1, but only 2-fold when catalyzed by CYP2C6. Isoflurane had no stimulatory effect on benzphetamine metabolism by CYP2B1 or CYP2C6. Cytochrome b5 was not required for isoflurane-facilitated CDE metabolism; however, the addition of cytochrome b5 to CYP2B1 increased CDE metabolism 71 and 44%, in the absence and presence of isoflurane, respectively. In reconstituted CYP2B1, isoflurane generated a type I difference spectrum of approximately twice the magnitude of CDE and stimulated NADPH consumption more so than CDE. The same quantity of NADPH was consumed when CDE was present with isoflurane as compared with isoflurane alone. These data support the hypothesis that isoflurane stimulates CDE metabolism by a mechanism involving increased P450 reduction via direct isoflurane interaction with P450.

Short-chain saturated halocarbons, including isoflurane and the chlorofluorocarbon substitute HCFC-123, can strongly potentiate the cytochrome P450-dependent oxidation of gaseous haloethenes, such as 2-chloro-1,1-difluoroethene (CDE) and vinyl chloride, in vivo and in vitro. P450 isozyme specificity in this effect is suggested by the fact that the interaction is pronounced in microsomes from rats treated with phenobarbital, but does not occur in microsomes of isoniazid- or beta-naphthoflavone-treated animals. We examined the effect of isoflurane on CDE defluorination in liver microsomes from 10 human organ donors to determine whether saturated halocarbon/haloethene interactions also occur in humans and, if so, to determine the cytochromes P450 involved. Three of the samples exhibited isoflurane-stimulated increases (24, 32, and 41%) in CDE defluorination; isoflurane either inhibited or had no effect on CDE metabolism in the other seven samples. Two samples in which isoflurane potentiated CDE metabolism to the greatest rates had higher coumarin 7-hydroxylase (indicative of CYP2A6), 7-ethoxycoumarin O-deethylase (CYP2B6), and nifedipine oxidase (CYP3A4) activities than the other eight samples. However, all 10 subjects had similar rates of phenacetin O-deethylation (CYP1A2) and chlorzoxazone 6-hydroxylation (CYP2E1). In microsomes from cells transfected with cDNAs coding for individual human P450s, CDE metabolism by CYP2B6 was stimulated (216%) by isoflurane, whereas isoflurane did not stimulate CDE metabolism by human CYP2A6, CYP3A4, CYP2D6, or CYP2E1. Isoflurane highly increased CDE defluorination in purified rat CYP2B1 (470%).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of propofol on cytochrome P450 activity in rat hepatic microsomes were evaluated to determine the potential influence of this anesthetic on the metabolism of coadministered agents. In microsomes from untreated and isoniazid-treated rats, propofol was a weak inhibitor of enflurane metabolism, inhibiting activity only at 0.35 mM propofol. In contrast, toluene, a related compound, effectively impaired enflurane defluorination in microsomes from untreated, and isoniazid- and phenobarbital-treated rats at concentrations as low as 0.025 mM. Propofol, in contrast to toluene, was an effective inhibitor of benzphetamine demethylation where it inhibited this activity at propofol concentrations as low as 0.025 mM in microsomes from phenobarbital-treated rats. In microsomes from phenobarbital-treated rats, propofol potently inhibited the metabolism of aniline. Sixty-four percent inhibition was achieved at 0.03 mM propofol, whereas toluene had no effect at 1 mM. These data demonstrate that propofol does not effectively inhibit enflurane metabolism performed by the isoniazid-inducible cytochrome P450IIE1 but effectively impairs activities of the phenobarbital-inducible cytochrome P450 isozymes.