Brain Uptake and Acute Indole‐depleting Effect of Dexfenfluramine in Squirrel Monkeys after a High‐dose Regimen

No studies have examined the brain uptake of dexfenfluramine in non‐human primates, although these species have been used to study the potential toxic effects of high doses on 5‐HT‐ergic neurons. Male squirrel monkeys were, therefore, given 5 mg kg⁻¹ dexfenfluramine, subcutaneously, twice daily, for four days and plasma was collected 2 h after the morning dose on each day. At the end of the study all animals were killed and the brains were removed for drug and indole analysis. Plasma concentrations of dexfenfluramine and its active metabolite dexnorfenfluramine rapidly built up, reaching steady‐state total concentrations (parent drug + metabolite) of approximately 1·4 μg mL⁻¹ within two to three days. This indicated that monkeys were exposed to very high multiples (about 14) of the total therapeutic plasma concentrations. The mean brain‐to‐plasma ratios of dexfenfluramine (23) and dexnorfenfluramine (25) were high in this primate, coming close to that in rodents but higher than seen in two suicide cases after a large dose of fenfluramine (about 8–10). It is thus likely that extrapolation of plasma concentrations from monkeys to man, like from rats to man, overestimates the human brain exposure to dexfenfluramine and its nor‐metabolite. Total brain concentrations in this primate greatly exceeded those in rats and particularly mice given the same regimen of dexfenfluramine. The acute indole‐depleting effects of dexfenfluramine were also greater in whole brain of squirrel monkeys (≥ 90%) than in sensitive telencephalic regions of rats (75–86%) and mice (50%). These findings suggest that species differences in dexfenfluramine disposition are a major factor in the neurochemical response to the drug, its extent possibly being governed by the exposure of the target site to critical concentrations of the parent compound and its nor‐derivative. 1995 Royal Pharmaceutical Society of Great Britain