Effect of diazepam treatment on hepatic microsomal anesthetic defluorinase activity

Different dosing regimens with diazepam were evaluated in male Fischer 344 rats for their ability to enhance the metabolism of several inhalation anesthetics. In vitro metabolism was assessed by the rate of microsomal anesthetic defluorination as measured by the appearance of inorganic fluoride ion (i.e., defluorinase activity). Single daily doses of diazepam, 40 mg/kg, were delivered by gavage for either 7 or 14 days; more continuous dosing was achieved by administration of diazepam at 0.03% or 0.10% in food pellets. Hepatic microsomes isolated from treated rats showed significant dose-related elevations in methoxyflurane defluorinase activity, but not in enflurane or isoflurane defluorinase activities. The microsomal content of cytochromes P-450 and b5 and the NADPH-cytochrome-c-reductase activity was not significantly different among treated and untreated groups. Para-nitroanisole O-demethylase activity expressed per nmole cytochrome P-450 increased in the diazepam-treated groups. Extrapolation of these animal data to humans suggests that surgical patients treated chronically with diazepam are probably not at increased risk for inorganic fluoride-induced nephrotoxicity due to increased metabolism of the fluorinated inhalation anesthetics.