The toxicity and metabolism of the fluorinated anesthetic methoxyflurane were compared in Fischer 344 rats pretreated with phenytoin [DPH] or phenobarbital. Treatment with either drug potentiated the polyuric effects of methoxyflurane by more than 100%. Also, serum F- levels and urinary F- excretions after methoxyflurane exposure were comparable in DPH and phenobarbital-treated rats, a 26-49% increase as compared to rats treated with methoxyflurane alone. In vitro, 10-fold increases in the rate of hepatic microsomal methoxyflurane defluorination were observed after treatment of rats with either DPH or phenobarbital. Kinetic studies with microsomes demonstrated inhibition of methoxyflurane defluorination in the presence of DPH. Defluorination of 3 additional fluorinated ether anesthetics, enflurane, isoflurane and sevoflurane, also was examined in vitro. DPH and phenobarbital treatment resulted in similar enhancement of defluorination of the latter 2 anesthetics, but not enflurane. DPH and phenobarbital treatment increases defluorination of fluorinated ether anesthetics to approximately the same extent in vitro and in vivo in Fischer 344 rats.