Pharmacokinetics of Selective Serotonin Reuptake Inhibitors: Clinical Relevance

Abstract

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 IA2, 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.

Pharmacokinetics of Fluoxetine in Elderly Men and Women

“…Because this study evaluated only elderly subjects with no younger comparison group, and because our subjects did not reach steady state drug levels, it is diffi cult to compare values between studies. Our observations on the timing of the maximum concentrations at each visit of fl uoxetine, norfl uoxetine and their combined values support the observations cited earlier that it might take a considerable amount of time to reach steady state in the elderly [8,9] . The plasma concentrations reached in our elderly subjects are considerably higher than that previously reported by Harvey and Preskorn [8] for subjects receiving repeated doses of 40 mg a day, albeit with a different dose schedule.…”

Stereoselective Pharmacokinetics of Fluoxetine and Norfluoxetine Enantiomers in Pregnant Sheep

“…These differences could in part be due to variations in drug administration regimens. FX clearance decreases and t 1/2 increases in humans with chronic drug dosing (Catterson and Preskorn, 1996;Hiemke and Härtter, 2000), and this appears due to FX-induced inhibition of CYP2D6 (Alfaro et al, 2000). We have observed a similar decrease in FX clearance in sheep during an 8-day i.v.…”

“…Currently there are five serotonin reuptake inhibitors (SSRIs 3 ) available worldwide with fluoxetine (Prozac; Eli Lilly & Co., Indianapolis, IN) being the first SSRI introduced in the North American market in 1987 (Catterson and Preskorn, 1996;Hiemke and Härtter, 2000). More than a decade after its introduction, fluoxetine (FX) still remains one of the most frequently prescribed antidepressants of this class for the treatment of depressive, obsessive-compulsive, and eating disorders.…”

Long-Term Outcomes of Developmental Exposure to Fluoxetine: A Review of the Animal Literature

“…To provide one example, a dose given orally will be subject to first-pass metabolism by cytochrome P450 enzymes in the liver, which are more active during pregnancy [71], and as such will result in a lower concentration than a dose administered by intraperitoneal injection or outside the pregnant state. Further complicating the issue, cytochrome P450 is inhibited by FLX, producing a non-linear relationship between drug dosage and drug concentration [72]. Additionally, stress is induced by some methods of administration, such as gavage [73] and injection [74], whereas other methods, such as administering FLX in the drinking water, are non-intrusive.…”