EFFECT OF D-FENFLURAMINE ON THE INDOLE CONTENTS OF THE RAT-BRAIN AFTER TREATMENT WITH DIFFERENT INDUCERS OF CYTOCHROME-P450 ISOENZYMES

The effects of pretreatment with inducers of hepatic cytochrome P450 isoenzymes (phenobarbital, dexamethasone and beta-naphthoflavone) on the metabolism of d-fenfluramine (d-F) and its acute and long-lasting indole-depleting effects were studied in rats, in an effort to obtain further information on the importance of hepatic drug metabolism in relation to its neurochemical actions. Twenty-four hours after the last dose of each inducer, rats were injected with d-F hydrochloride (5 mg/kg, IP) and killed at various times thereafter for parallel determination of indoles and drug concentrations in plasma and brain. Additional rats were treated as above and killed 1 week after d-F hydrochloride (5 and 10 mg/kg) to study the recovery of indole in the cortex, a particularly sensitive brain area. Phenobarbital and beta-naphthoflavone and, to a lesser degree, dexamethasone, stimulated the metabolism of d-F, as evidenced by a decrease in plasma and brain areas under the curve (AUC) compared to vehicle-treated rats. This indicated that multiple isoenzymes are capable of mediating the drug's metabolism, primarily by N-dealkylation to d-norfenfluramine (d-NF). None of the inducers raised plasma and brain AUC of the nor-derivative, and in fact phenobarbital and particularly beta-naphthoflavone reduced it. These different effects were even apparent in rats given d-NF (2.5 mg/kg), indicating that both phenobarbital and beta-naphthoflavone also stimulate the sequential metabolism of the nor-metabolite (by N-deamination) which, however, is apparently enhanced most actively by beta-naphthoflavone-inducible forms of P-450. Total ''active'' brain concentrations (d-F + d-NF) after the different pretreatments were in the order of beta-naphthoflavone < phenobarbital < dexamethasone less than or equal to vehicle. Interestingly, beta-naphthoflavone rapidly reversed the depletion of brain indoles caused by d-F (and d-NF); phenobarbital provided partial protection and dexamethasone did not appreciably modify either the acute or long-term neurochemical effects of the drug. The fact that phenobarbital affected d-NF kinetics less than beta-naphthoflavone, and provided only partial protection against the acute and long-lasting neurochemical effects of high doses of d-F, further stresses the critical role of d-NF in the neurochemical outcome of its parent drug. These findings support the view that the degree and duration of the indole-depleting effects are related to critical brain concentrations of the parent compound and its nor-derivative, and provide indirect evidence that hepatic metabolites other than d-NF are unlikely to play any role in the neurochemical effects of high doses of d-F in rats.