SSRIs steady state

SSRis Time to peak piasma concentration (h) Haif-iife (h) Protein binding (%) Time to reach steady state (days) Primary route of eiimination... 

Paroxetine at low concentration is dependent on CYP 2D6 for its clearance. However, this enzyme is almost completely saturated by paroxetine at low concentrations, which accounts for the nonlinear pharmacokinetics of paroxetine and why its half-life goes from 10 to 20 hours when the dose is advanced from 10 to 20 mg per day. At higher concentrations, paroxetine is most likely dependent on CYP 3A3/4 for its clearance. This dose-dependent change in the clearance of paroxetine probably accounts for the higher incidence of withdrawal reactions with this SSRI than might otherwise be expected for a drug with a half-life of 20 hours at steady-state on 20 mg per day (296, 297). 

Another difference between the SSRI antidepressants is their half-lives. Paroxetine has a half-life of approximately one day, sertraline one to two days, and fluoxetine seven to ten days. A long half-life is an advantage in maintaining a stable blood level but a disadvantage when starting or stopping the mediciaton. It takes six weeks to reach a steady state with fluoxetine. 

Sertraline and fluoxetine undergo metabolic demethylation. Unlike the metabolites of most other SSRIs, the desmethyl metabolite of fluoxetine, norfluoxetine(34), retains the ability to inhibit serotonin reuptake (205). Hence, fluoxetine takes longer to achieve steady-state levels, and it retains activity after metabolism. The half-life of fluoxetine is approximately 1 day, but elimination of norfluoxetine is prolonged (7-15 days) (205). In addition to its actions as an SSRI, norfluoxetine also binds at 5-HT, receptors (127). 

Paroxetine. The concurrent use of paroxetine 20 mg daily and duloxetine 40 mg daily increased the AUC of duloxetine at steady state by about 60% in healthy subjects. Paroxetine is an inhibitor of CYP2D6, which has a role in duloxetine metabolism. Therefore concurrent use raises duloxetine levels. The rise in duloxetine levels with paroxetine 20 mg daily is probably not clinically relevant, but the manufacturer notes that greater increases would be expected with higher doses. Caution is warranted. Other SSRIs (notably fluoxetine) also inhibit this isoenzyme, and would therefore be expected to interact similarly. 

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