Clinical isoflurane metabolism by cytochrome P450 2E1

Background Some evidence suggests that isoflurane metabolism to trifluoroac etic acid and inorganic fluoride by human liver microsomes in vitro is cata lyzed by cytochrome P450 2E1 (CYP2E1). This investigation tested the hypoth esis that P450 2E1 predominantly catalyzes human isoflurane metabolism iii vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P4 50 2E1, was used as a metabolic probe for P450 2E1. Methods: Twenty-two elective surgery patients who provided institutionally- approved written Informed consent were randomized to receive disulfiram (50 0 mg orally, N = 12) or nothing (controls, N = 10) the evening before surge ry, All patients received a standard isoflurane anesthetic (1.5% end-tidal in oxygen) for 8 hr. Urine and plasma trifluoroacetic acid and fluoride con centrations were quantitated in samples obtained for 4 days postoperatively , Results: Patient groups were similar with respect to age, weight, gender, d uration of surgery, blood loss, and delivered isoflurane dose, measured by cumulative end-tidal isoflurane concentrations (9.7-10.2 MAC-hr). Postopera tive urine excretion of trifluoroacetic acid (days 1-4) and fluoride (days 1-3) was significantly (P < 0.05) diminished in disulfiram-treated patients . Cumulative 0-96 hr excretion of trifluoroacetic acid and fluoride in disu lfiram-treated patients was 34 +/-72 and 270 +/- 70 mu moles (mean +/- SD), respectively, compared to 440 +/- 360 and 1500 +/- 800 mu moles in control s (P < 0.05 for both). Disulfiram also abolished the rise In plasma metabol ite concentrations, Conclusions: Disulfiram, a selective inhibitor of human hepatic P450 2E1, p revented 80-90% of isoflurane metabolism. These results suggest that P450 2 E1 is the predominant P450 isoform responsible for human clinical Isofluran e metabolism in vivo.