Metabolism, Excretion, and Pharmacokinetics of Duloxetine in Healthy Human Subjects

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake being investigated for the treatment of depression and urinary incontinence. The disposition of duloxetine was studied in four healthy human subjects after a single 20.2-mg (100.6 Ci) oral dose of [ 14 C]duloxetine in an enteric-coated tablet. The mean total recovery of radioactivity (؎ S.E.M.) after 312 h was 90.5% (؎0.4%) with 72.0% (؎1.1%) excreted in the urine. Duloxetine was extensively metabolized to numerous metabolites primarily excreted into the urine in the conjugated form. The major biotransformation pathways for duloxetine involved oxidation of the naphthyl ring at either the 4-, 5-, or 6-positions followed by further oxidation, methylation, and/or conjugation. The major metabolites found in plasma were glucuronide conjugates of the following: 4-hydroxy duloxetine (M6), 6-hydroxy-5-methoxy duloxetine (M10), 4, 6-dihydroxy duloxetine (M9), and a sulfate conjugate of 5-hydroxy-6-methoxy duloxetine (M7). The major metabolites found in plasma were also found in the urine, but the urine contained many additional metabolites. In addition to duloxetine, 4-hydroxy duloxetine (M14) and an unidentified polar metabolite were observed in feces. Following [ 14 C]duloxetine administration, C max was reached at a median of 6 h for both duloxetine and total radioactivity. Duloxetine accounted for less than 3% of the circulating radioactivity based on mean area under the curve values. The elimination half-life of total radioactivity (120 h) was substantially longer than that of duloxetine (10.3 h).

Comparison of the Anti-tumor Effects of Selective Serotonin Reuptake Inhibitors as Well as Serotonin and Norepinephrine Reuptake Inhibitors in Human Hepatocellular Carcinoma Cells

“…[20][21][22][23] The plasma concentrations (in µM) after the administration of the SNRIs duloxetine and milnacipran have been reported to be 0.0704±0.0422 and 0.847±0.117, respectively. 24,25) In the present study, the order of cytotoxicity in HepG2 cells was sertraline, paroxetine, and duloxetine, with IC 50 values (in µM) of 1.24, 7.34, and 8.95, respectively. The plasma concentration of sertraline was about one-half that of paroxetine, and nearly equal to that of duloxetine.…”

A Rare Case of Possible, Food, Drug and Acrylamide Pharmacological Interactions

“…The patient also takes tea in unknown quantities, which also makes uncertain caffeine's concentration present in her body, besides the known quantity ingested with paracetamol ( Figure 2). The pharmacokinetic interactions themselves may explain the patient's symptoms and signs, for instance duloxetine is metabolized via glucuronidation, acrylamide is metabolized by either phase 1 (CYP-450) or 2 reactions, in phase 2, the enzyme involved is a glutathione transferase, paracetamol is metabolized by two enzymes in two independent phase two reactions glutathione and glucuronyl transferases, cyclobenzaprine is glucuronidated and caffeine is metabolized by CYP-450 (Figure 2) [3,[10][11][12].…”

“…The pharmacotherapy for such disorder usually starts with one single drug and during the course of the treatment it might become necessary to escalate not only dosing but onto other drugs, in doing this, the chances of drug-drug interaction increase [3,4]. For example a patient may receive cyclobenzaprine, paracetamol+caffeine, the first one as a relaxant and the second to clearly mitigate the pain.…”

Getting the balance right: Established and emerging therapies for major depressive disorders

“…136 Generally, the tolerability profiles of bupropion and SSRIs are similar, although bupropion is associated with more headache and dry mouth. 115,120 However, sexual dysfunction following SSRIs is not a problem with bupropion, 151 and lower rates of somnolence and diarrhea are associated with this agent. 151 Similar incidences of adverse events were reported for bupropion and venlafaxine.…”