Duloxetine: A Balanced and Selective Norepinephrine and Serotonin-Reuptake Inhibitor

Anders D. Westanmo; Jon Gayken; Robert Haight

Disclosures

Am J Health Syst Pharm. 2005;62(23):2481-2490. 

In This Article

Pharmacokinetics

Absorption of duloxetine begins two hours after oral administration, and the maximum concentration in plasma (Cmax) is achieved in approximately six hours.[25] Administration of duloxetine with a meal does not alter the Cmax but increases the time to peak absorption by 6–10 hours and decreases the area under the concentration-versus-time curve (AUC) by 10%.[25] Administration of duloxetine in the evening rather than the morning causes a three-hour delay in absorption and increases clearance by approximately 33%.[25]

The estimated volume of distribution is 1640 L, although there was large variability among subjects (range, 11–50 L/kg).[25,33] Duloxetine is highly protein bound (> 90%), primarily to albumin or 1-acid-glycoprotein.[24]

Duloxetine undergoes rapid metabolism after absorption and has a half-life of about 12 hours (range, 8–17 hours).[25] It is metabolized primarily by cytochrome P-450 (CYP) isoenzymes 2D6 and 1A2.[25,34] Although most duloxetine metabolites (70%) are excreted in the urine, approximately 20% are excreted in the feces.[35] Duloxetine itself accounted for only 3% of the AUC and 9% of the Cmax after ingestion of a 20-mg tablet.[35] One study of the metabolism of duloxetine identified at least 25 metabolites, most of which were renally eliminated glucuronide conjugates.[35] To date, none of the proposed major metabolites (any metabolite constituting > 1% of the total) has shown appreciable receptor activity.[35–37]

processing....