CLINICALLY RELEVANT PHARMACOLOGY OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS - AN OVERVIEW WITH EMPHASIS ON PHARMACOKINETICS AND EFFECTS ON OXIDATIVE DRUG-METABOLISM

This paper presents an overview of the clinically relevant pharmacolog y of selective serotonin reuptake inhibitors (SSRIs) with an emphasis on their pharmacokinetics and effects on cytochrome P450 (CYP) enzymes . The SSRIs are potent inhibitors of the neuronal reuptake pump for se rotonin (5-hydroxytryptamine; 5-HT) and have minimal effects on a numb er of other sites of actions (e.g. neuroreceptors and fast sodium chan nels). For this reason, drugs in this class have remarkable similarity as regards acute and maintenance antidepressant efficacy and tolerabi lity profile. However, individual members of this class differ substan tially in their pharmacokinetics and effects on CYP enzymes. Most SSRI s have a half-life (t1/2) of approximately 1 day. Fluoxetine, however, has a longer t1/2 of 2 to 4 days, and its active metabolite, norfluox etine, has an extended t1/2 of 7 to 15 days. Fluoxetine, paroxetine an d, to a lesser extent, fluvoxamine inhibit their own metabolism. That is not the case for citalopram or sertraline. There are nonlinear incr eases in paroxetine plasma concentrations with dosage increases, but p roportional changes with citalopram and sertraline. Indirect data sugg est that fluoxetine and fluvoxamine also have nonlinear pharmacokineti cs over their usual dosage range. Age-related increases in plasma drug concentrations for citalopram (approximate to 130%) and paroxetine (a pproximate to 50 to 100%) have been observed in healthy elderly (65 to 75 years) persons versus those who are younger. There is an age-gende r interaction for sertraline, with its plasma concentrations being 35 to 40% lower in young men than in elderly or young females or elderly males. While there is no apparent change in fluvoxamine plasma levels as a function of age, plasma drug concentrations are 40 to 50% lower i n males than in females. Limited data from clinical trials suggest tha t age-related differences with fluoxetine may be comparable to those o f citalopram and paroxetine. Marked differences exist between the SSRI s with regard to effects on specific CYP enzymes and, thus, the likeli hood of clinically important pharmacokinetic drug-drug interactions. T he most extensive in vitro and in vivo research has been done with flu oxetine, fluvoxamine and sertraline; there has been less with paroxeti ne and citalopram. The available in vivo data at each drug's usually e ffective antidepressant dose are summarised below. Citalopram produces mild inhibition of CYP2D6. Fluvoxamine produces inhibition (which wou ld be expected to be clinically meaningful) of two CYP enzymes, CYP1A2 and CYP2C19, and probably a third, CYP3A3/4. Fluoxetine substantially inhibits CYP2D6 and probably CYP2C9/10, moderately inhibits CYP2C19 a nd mildly inhibits CYP3A3/4. Paroxetine substantially inhibits CYP2D6 but does not appear to inhibit any other CYP enzyme. Sertraline produc es mild inhibition of CYP2D6 but has little, if any, effect on CYP1A2, CYP2C9/10, CYP2C19 of CYP3A3/4. Understanding the similarities and di fferences in the pharmacology of SSRIs can aid the clinician in optima l use of this important class of antidepressants.