PHARMACOKINETICS OF THE NEWER ANTIDEPRESSANTS - CLINICAL RELEVANCE

The newer antidepressants are a diverse group of compounds with distin ct pharmacokinetic properties. The selective serotonin reuptake inhibi tors (SSRIs)-paroxetine, sertraline, and fluvoxamine-have elimination half-lives of 15-26 hours. The extended half-life of fluoxetine (4-6 d ays) and its active metabolite, norfluoxetine (4-16 days), results in an extended time to steady-state and a prolonged washout period when d osing is discontinued. The SSRIs are administered as a single daily do se. Venlafaxine and nefazodone have short half-lives, 2-5 hours, and a re dosed greater than or equal to 2 times daily. The newer antidepress ants are all highly cleared from the body through hepatic metabolism. The biotransformation of all the drugs except paroxetine and fluvoxami ne results in the. formation of pharmacologically active metabolites. The newer antidepressants display a broad variability similar to the t ricyclic antidepressants (TCAs) in steady-state drug concentrations. D ue largely to a safer toxicity profile, the variability in clearance i s of lesser importance with the newer antidepressants than with the TC As. No useable concentration. versus therapeutic effect relationship h as been found with the newer drugs, and widely varying concentrations appear to have little relationship to adverse effects. Knowledge of ki netic characteristics is important for designing dosage regimens and a voiding potentially serious drug-drug interactions that are mediated t hrough inhibition of specific hepatic cytochrome P450 enzyme pathways; Each of the SSRIs inhibits at least one cytochrome P450 enzyme, and a ll of the SSRIs increase serum concentrations of concomitantly adminis tered TCAs.