Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers

• Published in: Clinical pharmacology and therapeutics Vol. 73; no. 3; pp. 170 - 177
• Main Authors: Skinner, Michael H., Kuan, Han‐Yi, Pan, Alan, Sathirakul, Korbtham, Knadler, Mary Pat, Gonzales, Celedon R., Yeo, Kwee Poo, Reddy, Shobha, Lim, Maggie, Ayan‐Oshodi, Mosun, Wise, Stephen D.
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01-03-2003
• Subjects: Adult; Antidepressive Agents, Tricyclic - administration & dosage; Antidepressive Agents, Tricyclic - blood; Antidepressive Agents, Tricyclic - pharmacokinetics; Area Under Curve; Biological and medical sciences; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2D6 Inhibitors; Desipramine - administration & dosage; Desipramine - blood; Desipramine - pharmacokinetics; Drug Administration Schedule; Drug Interactions; Duloxetine Hydrochloride; Female; Humans; Male; Medical sciences; Middle Aged; Neuropharmacology; Paroxetine - administration & dosage; Paroxetine - blood; Paroxetine - pharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Reference Values; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - blood; Serotonin Uptake Inhibitors - pharmacokinetics; Serotonin Uptake Inhibitors - pharmacology; Thiophenes - administration & dosage; Thiophenes - blood; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; Human; Paroxetine; Drug combination; Healthy subject; Serotonin; Desipramine; Enzyme; Isozyme; Psychotropic; Toxicity; Cytochrome P450; Oral administration; Genotype; Duloxetine; Tricyclic compound; Reuptake inhibitor; Metabolism; Piperidine derivatives; Antidepressant agent; Drug interaction; Pharmacokinetics
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1067/mcp.2003.28

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.
Clinical Pharmacology & Therapeutics (2003) 73, 170–177; doi: 10.1067/mcp.2003.28