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The selective serotonin reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine have varying degrees of potency in inhibiting the hepatic cytochrome P450 (CYP) 2D6 enzyme. However, the time course for maximum inhibition to occur or for inhibition to dissipate when dosing is discontinued, requires clarification. In an open label, parallel group study of 45 healthy volunteers, the time course of CYP2D6 inhibition of the above SSRIs was evaluated. Subjects were randomized to receive paroxetine at 20 mg/day for 10 days; sertraline at 50 mg/day for 3 days, followed by sertraline at 100 mg/day for 10 days; or fluoxetine at 20 mg/day for 28 days. CYP2D6 activity was assessed using the dextromethorphan metabolic ratio (DMR) on antidepressant days 5 and 10 for sertraline and paroxetine and at weekly intervals for fluoxetine. Following SSRI discontinuation, calculation of a CYP2D6 inhibition half-life (t½inh) revealed the time course of fluoxetine inhibition (t½inh = 7.0 ± 1.5 days) to be significantly longer than either paroxetine (t½inh = 2.9 ± 1.9) or sertraline (t½inh = 3.0 ± 3.0) (p < 0.01), but the latter were not significantly different from each other (p > 0.05). Time for the extrapolated DMR versus time loglinear plots to return to baseline was significantly different between fluoxetine (63.2 ± 5.6 days) and both paroxetine (20.3 ± 6.4 days) and sertraline (25.0 ± 11.0 days) (p < 0.01), making the rank order (from longest to shortest) of time for CYP2D6 inhibition to dissipate: fluoxetine > sertraline ≥ paroxetine. Differences between mean baseline DMR values and measured values obtained after drug discontinuation for each drug group became nonsignificant on discontinuation day 5 for both paroxetine and sertraline and on discontinuation day 42 for fluoxetine. These data define the time course of a persistent effect that fluoxetine, sertraline, and paroxetine have on CYP2D6 following drug discontinuation and should be considered when initiating therapy with a CYP2D6 substrate.