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. The total brain drug concentration (d-fenfluramine + d-norfenfluramine) after 2.5 mg/kg d-fenfluramine was closed - although the metabolite-to-parent drug ratios differed in vehicle- and SKF-525-treated animals - to that of the metabolite concentration after synthetic d-norfenfluramine, but d-fenfluramine had a weaker neurochemical effect (12-16% depletion of 5-HT only) than d-norfenfluramine (about 30-40% reduction of both indoles). These findings suggest that the neurochemical response to d-fenfluramine is dependent on critical brain concentrations of both d-fenfluramine and d-norfenfluramine, the metabolite playing a major role in the indole-depleting effect of the parent compound.