Michael H. Skinner, MD, PharmD [MEDLINE LOOKUP]
Background and Objectives: Duloxetine, a potent dual reuptake
inhibitor of serotonin and norepinephrine currently undergoing clinical
investigation for treatment of depression and stress urinary incontinence, has
the potential to act as both a substrate and an inhibitor of cytochrome P4502D6
(CYP2D6). Our objectives were to determine the effect of duloxetine on the
pharmacokinetics of desipramine, a tricyclic antidepressant metabolized by
CYP2D6 (study 1), and the effect of paroxetine, a potent CYP2D6 inhibitor, on
duloxetine pharmacokinetics (study 2).
Methods: Subjects were healthy men and women between 21 and 63 years old. All subjects were genotypically CYP2D6 extensive metabolizers. In study 1, 50 mg of desipramine was administered as a single dose alone and in the presence of steady-state duloxetine 60 mg twice daily. In study 2, steady-state pharmacokinetics of duloxetine 40 mg once daily were determined in the presence and absence of steady-state paroxetine 20 mg once daily.
Results: Duloxetine increased the maximum plasma concentration of desipramine 1.7-fold and the area under the concentration-time curve 2.9-fold. Paroxetine increased the maximum plasma concentration of duloxetine and the area under the concentration-time curve at steady state 1.6-fold. Reports of adverse events were similar whether duloxetine was administered alone or in combination with desipramine or paroxetine.
Conclusion: Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine. (Clin Pharmacol Ther 2003;73:170-7.)
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Copyright © 2003 by the American Society for Clinical Pharmacology & Therapeutics.