M. Anelli et al., EFFECT OF D-FENFLURAMINE ON THE INDOLE CONTENTS OF THE RAT-BRAIN AFTER TREATMENT WITH DIFFERENT INDUCERS OF CYTOCHROME-P450 ISOENZYMES, Psychopharmacology, 118(2), 1995, pp. 188-194
The effects of pretreatment with inducers of hepatic cytochrome P450 i
soenzymes (phenobarbital, dexamethasone and beta-naphthoflavone) on th
e metabolism of d-fenfluramine (d-F) and its acute and long-lasting in
dole-depleting effects were studied in rats, in an effort to obtain fu
rther information on the importance of hepatic drug metabolism in rela
tion to its neurochemical actions. Twenty-four hours after the last do
se of each inducer, rats were injected with d-F hydrochloride (5 mg/kg
, IP) and killed at various times thereafter for parallel determinatio
n of indoles and drug concentrations in plasma and brain. Additional r
ats 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 partic
ularly 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 i
soenzymes are capable of mediating the drug's metabolism, primarily by
N-dealkylation to d-norfenfluramine (d-NF). None of the inducers rais
ed plasma and brain AUC of the nor-derivative, and in fact phenobarbit
al and particularly beta-naphthoflavone reduced it. These different ef
fects were even apparent in rats given d-NF (2.5 mg/kg), indicating th
at both phenobarbital and beta-naphthoflavone also stimulate the seque
ntial metabolism of the nor-metabolite (by N-deamination) which, howev
er, is apparently enhanced most actively by beta-naphthoflavone-induci
ble forms of P-450. Total ''active'' brain concentrations (d-F + d-NF)
after the different pretreatments were in the order of beta-naphthofl
avone < phenobarbital < dexamethasone less than or equal to vehicle. I
nterestingly, beta-naphthoflavone rapidly reversed the depletion of br
ain indoles caused by d-F (and d-NF); phenobarbital provided partial p
rotection and dexamethasone did not appreciably modify either the acut
e or long-term neurochemical effects of the drug. The fact that phenob
arbital affected d-NF kinetics less than beta-naphthoflavone, and prov
ided only partial protection against the acute and long-lasting neuroc
hemical effects of high doses of d-F, further stresses the critical ro
le of d-NF in the neurochemical outcome of its parent drug. These find
ings support the view that the degree and duration of the indole-deple
ting effects are related to critical brain concentrations of the paren
t compound and its nor-derivative, and provide indirect evidence that
hepatic metabolites other than d-NF are unlikely to play any role in t
he neurochemical effects of high doses of d-F in rats.