Pharmacokinetics:
Fluoxetine is well absorbed after oral administration. In man, following a single 40 mg dose, peak plasma concentrations of fluoxetine ranged from 15 to 55 ng/mL 6 to 8 hours after dosing (range=1.5 to 12 hours). The capsule and oral solution dosage forms of fluoxetine are bioequivalent. Food appears to affect the rate but not the extent of absorption.
Fluoxetine is extensively metabolized in the liver to norfluoxetine, and other, unidentified metabolites. Norfluoxetine, a desmethyl metabolite, is also a serotonin reuptake inhibitor; its pharmacological activity being similar to that of the parent drug. Norfluoxetine contributes to the long duration of action of fluoxetine. Elimination of metabolites occurs primarily in the urine with a smaller amount also being present in the feces.
Clinical Issues Related to Metabolism/Elimination:
The complexity of fluoxetine's metabolism has several consequences which may potentially affect its clinical use.
Accumulation and Slow Elimination:
The half-life of fluoxetine after a single dose is 2 days (range 1 to 4 days) and after multiple dosing 4 days (range 2 to 7 days). The corresponding values for norfluoxetine are similar after single and multiple dosing, i.e., 8.6 and 9.3 days (range 4 to 15 days). After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine and norfluoxetine ranged from 91 to 302 ng/mL and 72 to 258 ng/mL respectively. Plasma concentrations of fluoxetine were higher than those predicted from single dose studies, presumably because fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics.
Steady state plasma levels are attained after 4 to 5 weeks of continuous drug administration. Patients receiving fluoxetine at doses of 40 to 80 mg/day over periods as long as 3 years exhibited, on average, plasma concentrations similar to those seen among patients treated for 4 to 5 weeks.
Similarly because of the long half-lives of fluoxetine and norfluoxetine, it may take up to 1 to 2 months for the active drug substance to disappear from the body. This is of potential consequence in withdrawal of fluoxetine (see Warnings).
