| Popis: |
Four compounds forming metabolic intermediate complexes with cytochrome P-450 in vitro were studied for their effects on hepatic glutathione in the mouse. All four compounds depleted glutathione within 1–3 hr after administration. The effect was transient for piperonyl butoxide while lasting at least 24 hr for other compounds. Induction of the mixed-function oxidase system by phenobarbital had no effect on the glutathione-depleting actions of the compounds, but induction with 3-methylcholanthrene abolished the depletion seen with piperonyl hutoxide and SKF 525-A. For SKF 525-A, l -α-acetylmethadol (LAAM) and norLAAM, the persistent lowering of glutathione was paralleled by elevations in serum glutamic-pyruvic transaminase (SGPT) activity. This depletion of glutathione and subsequent elevations in SGPT were found to be strain and species dependent for SKF 525-A, LAAM and norLAAM. Compounds which complex with cytochrome P-450 in vitro may increase drug toxicities in vivo by mechanisms other than inhibition of oxidative drug metabolism. |
