ISSN:
1432-2072
Keywords:
d-Fenfluramine
;
Brain kinetics
;
Indole-depleting effect
;
Inducers of drug metabolism
;
Rat
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract The effects of pretreatment with inducers of hepatic cytochrome P450 isoenzymes (phenobarbital, dexamethasone andβ-naphthoflavone) on the metabolism ofd-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 withd-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 afterd-F hydrochloride (5 and 10 mg/kg) to study the recovery of indole in the cortex, a particularly sensitive brain area. Phenobarbital andβ-naphthoflavone and, to a lesser degree, dexamethasone, stimulated the metabolism ofd-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 byN-dealkylation tod-norfenfluramine (d-NF). None of the inducers raised plasma and brain AUC of the nor-derivative, and in fact phenobarbital and particularlyβ-naphthoflavone reduced it. These different effects were even apparent in rats givend-NF (2.5 mg/kg), indicating that both phenobarbital andβ-naphthoflavone also stimulate the sequential metabolism of the nor-metabolite (byN-deamintaion) which, however, is apparently enhanced most actively byβ-naphthoflavone-inducible forms of P-450. Total “active” brain concentrations (d-F+d-NF) after the different pretreatments were in the order ofβ-naphthoflavone 〈 phenobarbital 〈 dexamethasone ≤ vehicle. Interestingly,β-naphthoflavone rapidly reversed the depletion of brain indoles caused byd-F (andd-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 affectedd-NF kinetics less thanβ-naphthoflavone, and provided only partial protection against the acute and long-lasting neurochemical effects of high doses ofd-F, further stresses the critical role ofd-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 thand-NF are unlikely to play any role in the neurochemical effects of high doses ofd-F in rats.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF02245839
