Fluoxetine, widely known by its brand name Prozac, is a selective serotonin reuptake inhibitor (SSRI) used to treat various psychiatric conditions. Its pharmacokinetics—the processes of absorption, distribution, metabolism, and excretion (ADME)—define how the body handles the medication. Fluoxetine’s profile is unique among SSRIs due to a highly active metabolite and unusually long clearance times, which influence its therapeutic use and potential for drug interactions.
How Fluoxetine Enters the Body
Fluoxetine is administered orally and is readily absorbed, exhibiting a relatively high bioavailability of approximately 72%. Peak plasma concentrations (Tmax) typically occur between six and eight hours after a single dose.
While food does not significantly change the total amount of drug absorbed, it can slightly delay the Tmax. Therefore, fluoxetine can generally be taken with or without a meal without affecting its overall systemic exposure.
The Role of Norfluoxetine
A significant feature of fluoxetine’s profile is its transformation into norfluoxetine, also known as desmethylfluoxetine. This potent active metabolite continues to exert a therapeutic effect and contributes substantially to the drug’s overall clinical efficacy. Norfluoxetine often reaches concentrations in the blood that exceed those of the parent compound over time.
Fluoxetine is highly protein-bound, with about 94 to 95% of the drug molecules temporarily attaching to plasma proteins like albumin. This high level of binding influences distribution, meaning only the small unbound fraction is free to travel to the central nervous system. Norfluoxetine is also extensively bound to plasma proteins, creating a reservoir of active compound that is slowly released over an extended period.
How the Body Processes the Drug
The liver is the primary site for the drug’s metabolism, where fluoxetine is broken down and converted into norfluoxetine through N-demethylation. The specific enzymes responsible for this conversion belong to the Cytochrome P450 (CYP) system, with the CYP2D6 enzyme playing a major role. This metabolic pathway is important because fluoxetine and norfluoxetine are potent inhibitors of the same CYP2D6 enzyme that processes them.
This inhibitory effect is a clinically relevant aspect of fluoxetine’s pharmacokinetics. By inhibiting CYP2D6, fluoxetine can slow the metabolism of other medications that rely on this enzyme for clearance. This potential drug-drug interaction can lead to elevated and sometimes toxic levels of co-administered medications, such as certain beta-blockers, antipsychotics, or tricyclic antidepressants.
Understanding Drug Timing and Clearance
Fluoxetine and norfluoxetine are characterized by exceptionally long half-lives. The half-life of the parent drug, fluoxetine, is approximately one to four days after a single dose, increasing to four to six days with chronic use. The active metabolite, norfluoxetine, has an even longer half-life, ranging from seven to fifteen days.
This prolonged clearance time means that the concentration of both compounds continues to build up over many weeks of consistent dosing. Consequently, the drug takes a substantial time—often several weeks—to reach a steady state, where the amount entering the body equals the amount eliminated. The long half-life of norfluoxetine dictates the need for a long washout period after treatment ends. Several weeks are required before certain other medications, such as monoamine oxidase inhibitors (MAOIs), can be safely started to avoid dangerous drug accumulation. Excretion of the drug and its metabolites occurs primarily through the urine.