Joytor-30/Joytor-60 Mechanism of Action

Antidepressant.
Pharmacology: Pharmacodynamics: Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals.
Neurochemical and behavioral studies in laboratory animals showed an enhancement of both serotonin and noradrenaline neurotransmission in the CNS. Duloxetine also normalized pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behavior in a model of persistent pain. The presumed mechanism of action of duloxetine in the treatment of both the emotional and somatic symptoms of depression is thought to be due to its inhibition of neuronal uptake of serotonin and noradrenaline, and a resultant increase in serotonergic and noradrenergic neurotransmission in the CNS.
Pharmacokinetics: Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolized by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of duloxetine demonstrate large intersubject variability (generally 50-60%), partly due to gender, age, smoking status and CYP2D6 metabolizer status.
Duloxetine is well absorbed after oral administration with a C_max occurring 6 hours post dose. The absolute oral max bioavailability max of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11%). These changes do not have any clinical significance.
Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds to both albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic impairment Duloxetine is extensively metabolized and the metabolites are excreted principally in urine. Both cytochromes P450-CYP2D6 and P450-CYP1A2 catalyze the formation of the two major metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5-hydroxy, 6-methoxy duloxetine.