Pharmacokinetics of selective serotonin reuptake inhibitors: Clinical relevance

Selective serotonin reuptake inhibitors (SSRIs) are a safe and effective class of drugs for treatment of depressive and obsessive-compulsive disorders. Among this class of drugs, pharmacodynamic actions, antidepressant efficacy and adverse effect profiles are remarkably similar. However, pharmacokinetic profiles of SSRIs are substantially different especially with respect to pharmacokinetically mediated drug-drug interactions. For example, fluoxetine and paroxetine produce clinically significant inhibition of cytochrome P450 2D6 at their usually effective antidepressant dose, whereas citalopram, fluvoxamine or sertraline do not. There is also a substantial difference between SSRIs with respect to their capacity to inhibit other cytochrome P450 enzymes including 1A2, 2C19, 3A4 and possibly 2C9/10. The inhibition of these enzymes can reduce the clearance of concomitantly administered drugs which are dependent on oxidative metabolism mediated by these enzymes as a necessary prerequisite for their subsequent elimination. The accumulation of unusually high levels of such drugs can result in an increase in nuisance and/or more serious, even life-threatening, adverse effects depending on the pharmacology of the co-prescribed drug. Knowledge of these issues will enable clinicians to predict and make appropriate dose adjustments to avoid potential drug-drug interactions that otherwise could result in toxicity.