Duloxetine Half-Life and Mechanism of Action
Half-Life
Duloxetine has an elimination half-life of approximately 12 hours (range 8 to 17 hours), allowing for once-daily dosing in most clinical situations. 1
- Steady-state plasma concentrations are typically achieved after 3 days of dosing 1
- The pharmacokinetics are dose proportional over the therapeutic range 1
- Most formulations have sufficiently long elimination half-lives to permit single daily dosing 2
Mechanism of Action
Duloxetine is a potent and balanced serotonin and norepinephrine reuptake inhibitor (SNRI) that increases the availability of both neurotransmitters in the central nervous system. 1
Primary Mechanism
- Duloxetine potently inhibits neuronal serotonin and norepinephrine reuptake, with approximately a 10:1 binding ratio for serotonin versus norepinephrine transporters 3
- It is a less potent inhibitor of dopamine reuptake 1
- The antidepressant, central pain inhibitory, and anxiolytic actions are believed to be related to potentiation of serotonergic and noradrenergic activity in the CNS 1
Receptor Profile
- Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, or GABA receptors 1
- It does not inhibit monoamine oxidase (MAO) 1
- This selective profile contributes to its relatively favorable side effect profile compared to older antidepressants 3
Clinical Implications of Mechanism
- The noradrenergic component modulates stress responses including alertness, arousal, attentiveness, and vigilance 2
- The serotonergic component plays a key role in the brain's ability to modulate fear, worry, and stress 2
- The dual mechanism provides efficacy across multiple pain conditions including diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain 4
Metabolism and Pharmacokinetic Considerations
- Duloxetine undergoes extensive hepatic metabolism involving two P450 isozymes: CYP1A2 and CYP2D6 1
- It is a moderate inhibitor of CYP2D6, requiring caution when combining with drugs metabolized by this pathway 2, 3
- Approximately 70% of the dose appears in urine as metabolites, with about 20% excreted in feces 1
- Only trace amounts (<1%) of unchanged duloxetine appear in urine 1