The role of d-norfenfluramine in the indole-depleting effect of d-fenfluramine in the rat.
The importance of d-norfenfluramine in regard to the indole-depleting action of d-fenfluramine has not been well studied in sensitive animal species. The present study therefore examined the intensity and time course of the neurochemical effects of i.p. injected d-fenfluramine (2.5 and 5 mg/kg) and d-norfenfluramine (2.5 mg/kg) in vehicle- and SKF-525A-pretreated rats, relating the effects to the brain concentration-time profiles of the drug and its active metabolite. At the lower dose d-fenfluramine caused only a small, short-lasting decrease in brain serotonin (5-HT) without affecting the 5-hydroxyindoleacetic acid (5-HIAA). Higher doses affected both 5-HT and 5-HIAA (50-60 and 30-40% reductions, respectively), the effect being maximal for at least 8 h. d-Norfenfluramine reduced the brain content of 5-HT and 5-HIAA less (by about 30%) than 5 mg/kg d-fenfluramine did. Brain concentrations of d-norfenfluramine at the time of the maximal depletion of indoles were close to those of the metabolite after 5 mg/kg d-fenfluramine, indicating that the acute indole-depleting effects did not depend solely on the brain concentrations of its nor-metabolite. SKF-525A changed the metabolite-to-parent drug ratios in brain without appreciably influencing the action of d-fenfluramine. However, the maximum decrease in indole content caused by 2.5 mg/kg d-fenfluramine in SKF-525A-pretreated rats was only 12% of the control level, although the brain concentration of unchanged drug was comparable to that after 5 mg/kg d-fenfluramine in vehicle-pretreated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Caccia
S
S
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Anelli
M
M
Ferrarese
A
A
Fracasso
C
C
Garattini
S
S
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D005277:Fenfluramine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007211:Indoles / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008297:Male; D009642:Norfenfluramine / Q000008:administration & dosage / Q000494:pharmacology*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism
D007211:Indoles; D009642:Norfenfluramine; D005277:Fenfluramine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D011335:Proadifen