Fluoxetine increases the anorectic and long-term dopamine-depleting effects of phentermine.
The anorectic drug phentermine produces dose-related toxic effects on brain dopamine (DA) neurons in animals. Until recently, phentermine was widely used in combination with fenfluramine for purposes of appetite suppression and weight loss. With the recent withdrawal of fenfluramine from the market, many people have begun combining phentermine with fluoxetine, a serotonin reuptake inhibitor which also produces mild anorectic effects. Fluoxetine, in addition to inhibiting serotonin reuptake, inhibits hepatic mixed function oxidase, which plays an important role in the metabolic degradation of amphetamines. The purpose of the present study was to assess the effects of fluoxetine on the anorectic and DA neurotoxic effects of phentermine in mice. Phentermine, in combination with fluoxetine, produced greater reductions in food intake and body weight than phentermine alone. The phentermine/fluoxetine combination also produced greater long-term reductions in brain DA levels than phentermine alone, likely reflecting greater DA neurotoxicity of the drug combination. Brain concentrations of phentermine were also found to be higher in animals pretreated with fluoxetine. These findings indicate that fluoxetine potentiates both the anorectic and DA neurotoxic effects of phentermine, probably by increasing phentermine brain levels. The clinical significance of these findings remains to be ascertained.
Callahan
B T
BT
Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21224, USA.
Yuan
J
J
Ricaurte
G A
GA
D000818:Animals; D000855:Anorexia / Q000139:chemically induced* / Q000503:physiopathology*; D001067:Appetite Depressants / Q000378:metabolism / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010645:Phentermine / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D001067:Appetite Depressants; D015306:Biogenic Monoamines; D018492:Dopamine Antagonists; D005473:Fluoxetine; D010645:Phentermine; D010088:Oxidoreductases