Pharmacokinetic drug interaction potential of selective serotonin reuptake inhibitors

Obsessive-compulsive disorder (OCD) is a chronic disorder requiring long-term treatment. The pharmacological management of the disorder, therefore, requires the use of agents which, in addition to being efficacious and well tolerated, are unlikely to cause pharmacokinetic drug-drug interactions with concomitantly administered medication which the patient is receiving or may receive in the future. The selective serotonin reuptake inhibitors (SSRIs) have similar pharmacodynamic profiles but their pharmacokinetic profiles are very different. Perhaps the most substantial pharmacokinetic difference among these drugs is in their potential for drug-drug interactions via the inhibition of cytochrome P450 (CYP) isoenzymes. This review provides comprehensive background information on these enzyme systems and discusses their significance with respect to the optimal care of patients. Fluoxetine is a substantial inhibitor of CYP2D6, has mild effects on CYP3A3/4, and may also have effects on CYP2C9/10 and CYP2C19. Effects on drugs metabolized by these enzymes can persist for many weeks after fluoxetine discontinuation due to the long half-life of fluoxetine and its active metabolite norfluoxetine. Fluvoxamine is a substantial inhibitor of CYP1A2 and CYP2C19, and a moderate inhibitor of CYP3A3/4. Paroxetine is a substantial inhibitor of CYP2D6. In contrast, sertraline and citalopram are mild inhibitors of CYP2D6 at their usually effective doses and are not known to produce clinically meaningful inhibition of any other isoenzymes. However, citalopram has not been well studied against all of these enzymes, especially in vivo. An increased risk of pharmacokinetic drug interactions is the immediate clinical consequence of the inhibitory effects of these drugs on CYP isoenzymes. However, with the emphasis on long-term treatment, particularly in chronic conditions such as OCD, it will also be important to determine the long-term clinical consequences of substantially inhibiting specific CYP isoenzymes with those SSRIs which have these effects. Thus knowledge of the substrates and inhibitors of CYP isoenzymes may help clinicians to anticipate and avoid pharmacokinetic drug interactions and may better define rational prescribing practices.