CLINICAL ENFLURANE METABOLISM BY CYTOCHROME-P450 2E1

Background: Fluorinated ether anesthetic hepatotoxicity and nephrotoxi city are mediated by cytochrome P450-catalyzed oxidative metabolism. M etabolism of the volatile anesthetic enflurane to inorganic fluoride i on by human liver microsomes in vitro is catalyzed predominantly by th e cytochrome P450 isoform CYP2E1. This investigation tested the hypoth esis that P450 2E1 is also the isoform responsible for human enflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selec tive inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1 . Methods: Twenty patients undergoing elective surgery were randomized to receive disulfiram (500 mg orally; n = 10) or nothing (control sub jects; n = 10) the evening before surgery. Ah patients received a stan dard anesthetic of enflurane (2.2% end-tidal) in oxygen for 3 hours. B lood enflurane concentrations were measured by gas chromatography. Pla sma and urine fluoride concentrations were quantitated by ion-selectiv e electrode, Results: Patient groups were similar with respect to age, weight, gender, duration of surgery, and blood loss. Total enflurane dose, measured by cumulative end-tidal enflurane concentrations (3.9 t o 4.1 MAC-hr) and by blood enflurane concentrations, was similar in bo th groups. Plasma fluoride concentrations increased fi om 3.6 +/- 1.5 mu mol/L (baseline) to 24.3 +/- 3.8 mu mol/L (peak) in untreated patie nts (mean +/- SE). Disulfiram treatment completely abolished the rise in plasma fluoride concentration. Urine fluoride excretion was similar ly significantly diminished in disulfiram-treated patients. Fluoride e xcretion in disulfiram-treated patients was 62 +/- 10 and 61 +/- 12 mu mol on days 1 and 2, respectively, compared with 1090 +/- 180 and 120 0 +/- 220 mu mol in control subjects (p < 0.05 on each day). Conclusio ns: Disulfiram prevented fluoride ion production after enflurane anest hesia. These results suggest that P450 2E1 is the predominant P450 iso form responsible for human clinical enflurane metabolism in vivo.