Pharmacokinetics of selective serotonin reuptake inhibitors

The five selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvo xamine, paroxetine, sertraline, and citalopram, have similar antidepressant efficacy and a similar side effect profile. They differ, however, in their pharmacokinetic properties. Under steady-state concentrations, their half- lives range between 1 and 4 days for fluoxetine (7 and 15 days for norfluox etine) and between 21 (paroxetine) and 36 (citalopram) hr for the other SSR Is. Sertraline and citalopram show linear and fluoxetine, fluvoxamine, and paroxetine nonlinear pharmacokinetics. SSRIs underlie an extensive metaboli sm with high interindividual variability, whereby cytochrome P450 (CYP) iso enzymes play a major role. Therefore, resulting blood concentrations are hi ghly variable between individuals. Except for N-demethylated fluoxetine, me tabolites of SSRIs do not contribute to clinical actions. Therapeutically e ffective blood concentrations are unclear so far, although there is evidenc e for minimal effective and upper-threshold concentrations that should not be exceeded. Paroxetine and, to a lesser degree, fluoxetine and norflouxeti ne are potent inhibitors of CYP2D6 and fluvoxamine of CYP1A2 and CYP2C19. T his can give rise to drug-drug interactions that may have no effect, lead t o intoxication, or improve the therapeutic response. These different pharma cokinetic properties of the five SSRIs, especially their drug-drug interact ion potential, should be considered when selecting a distinct SSRI for trea tment of depression or other disorders with a suggested dysfunction of the serotonergic system in the brain. (C) 1999 Elsevier Science Inc. All rights reserved.