Loxx 30/Loxx 60 Mechanism of Action

Pharmacology: Pharmacokinetics: Orally administered duloxetine is well absorbed but there is a median 2 hours lag until absorption begins. Food does not affect the peak plasma concentrations (C_max) of duloxetine, but delays the time to reach peak concentration (T_max) from 6 to 10 hours and it marginally decreases the extent of absorption [area under the curve (AUC)] by about 10%. Steady-state plasma concentrations are typically achieved after 3 days of dosing. There is a 3 hour delay in absorption of immediate release duloxetine, and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.
The apparent volume of distribution averages about 1640 L. Duloxetine (Loxx 30/Loxx 60) is highly bound (>90%) to proteins and binding is primarily to albumin and a1-acid glycoprotein.
Duloxetine (Loxx 30/Loxx 60) undergoes extensive metabolism and only about 3% of the total absorbed occurs as unchanged drug in plasma. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalize the oxidation of the naphthyl ring. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate.
Duloxetine (Loxx 30/Loxx 60) has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics is dose proportional over the therapeutic range. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine (Loxx 30/Loxx 60) undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.