title: Effect of d-fenfluramine on the indole contents of the rat brain after treatment with different inducers of cytochrome P450 isoenzymes.
abstract: 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-deamintaion) which, however, is apparently enhanced most actively by beta-naphthoflavone-inducible forms of P-450.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Instituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Anelli
authors.forename: C
authors.initials: C
authors.lastname: Fracasso
authors.forename: A
authors.initials: A
authors.lastname: Bergami
authors.forename: A
authors.initials: A
authors.lastname: Ferrarese
authors.forename: S
authors.initials: S
authors.lastname: Garattini
authors.forename: S
authors.initials: S
authors.lastname: Caccia
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology*; D001923:Brain Chemistry / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005277:Fenfluramine / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000032:analysis*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
chemical_list: D007211:Indoles; D007527:Isoenzymes; D005277:Fenfluramine; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital