The work which eventually led to the discovery of fluoxetine began at Eli Lilly in 1970 as a collaboration between Bryan Molloy and Robert Rathbun. It was known at that time that the antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized dozens of its derivatives. Testing the physiological effects of these compounds in mice resulted in nisoxetine, a selective norepinephrine reuptake inhibitor currently widely used in biochemical experiments.
Fluoxetine has been approved by the FDA for the treatment of major depression, obsessive compulsive disorder, bulimia nervosa and panic disorder. Fluoxetine was shown to be effective for depression in 6-week long double-blind controlled trials where it also alleviated anxiety and improved sleep. Fluoxetine was better than placebo for the prevention of depression recurrence when the patients, who originally responded to fluoxetine, were treated for a further 38 weeks. Efficacy of fluoxetine for geriatric as well as pediatric depression was also demonstrated in placebo-controlled trials.
3 dimensional representation of the cytochrome P450 isoenzyme CYP2D6. CYP2D6 is responsible for converting fluoxetine to its only active metabolite, norfluoxetine. Both drugs are also potent inhibitors of CYP2D6.
The bioavailability of fluoxetine is relatively high (72% in dogs), and peak plasma concentrations are reached in 6 to 8 hours. It is highly bound to plasma proteins, mostly albumin.
Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variability in the function of this enzyme among people. Only one metabolite of fluoxetine, norfluoxetine (demethylated fluoxetine), is biologically active.
According to the manufacturer of Prozac brand of fluoxetine Eli Lilly, fluoxetine is contraindicated in individuals taking monoamine oxidase inhibitors, pimozide (Orap) or thioridazine (Mellaril). The prescribing information recommends that the treatment of the patients with liver impairment “must be approached with caution”. The elimination of fluoxetine and its metabolite norfluoxetine is about twice slower in these patients, resulting in the proportionate increase of exposure to the drug. Ibuprofen used in combination with fluoxetine can cause significant intestinal bleeding after a period of use.
Fluoxetine and norfluoxetine inhibit many isozymes of the cytochrome P450 system that make drug metabolism possible. Both are potent inhibitors of CYP2D6 (the main enzyme responsible for their metabolism) and mild to moderate inhibitors of CYP1A2, CYP2B6, CYP2C9/2C19, and CYP3A4; furthermore, they inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism. This extensive effect on the body’s pathways for drug metabolism creates the potential for interactions with many commonly used drugs.