Pharmacotherapeutic Group: Other antidepressants. ATC Code: N06AX16.
Pharmacology: Pharmacodynamics: The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic or (alpha)-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.
Pharmacokinetics: Capsule: Venlafaxine is extensively metabolised, primarily to the active metabolite, O-desmethylvenlafaxine (ODV). Mean ± SD plasma half-lives of venlafaxine and ODV are 5 ± 2 hours and 11 ± 2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple dose therapy.
Absorption: At least 92% of venlafaxine is absorbed following single oral doses of immediate release venlafaxine. Absolute bioavailability is 40% to 45% due to presystemic metabolism. After immediate release venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively. Following the administration of venlafaxine prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. When equal daily doses of venlafaxine are administered as either an immediate release tablet or prolonged release capsule, the prolonged release capsule provides a slower rate of absorption, but the same extent of absorption are compared with the immediate release tablet. Food does not affect the bioavailability of venlafaxine and ODV.
Distribution: Venlafaxine and ODV are minimally bound at therapeutic concentrations to human plasma proteins (27% and 30%, respectively).
Metabolism: Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that venlafaxine is biotransformed to its major active metabolite, ODV, by CYP2D6; venlafaxine is metabolised to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4 and venlafaxine is a weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9, or CYP3A4.
Elimination: Venlafaxine and its metabolites are excreted primarily through the kidneys. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Mean ± SD plasma steady-state clearances of venlafaxine and ODV are 1.3 ± 0.6 l/h/kg and 0.4 ± 0.2 l/h/kg, respectively.
MR-FC Tablet: Venlafaxine is readily absorbed from the gastrointestinal tract. After oral doses, it undergoes extensive first pass metabolism in the liver mainly to the active metabolite ODV; formation of ODV is mediated by the cytochrome P450 isoenzyme CYP2D6. The isoenzyme CYP3A4 is also involved in the metabolism of venlafaxine. Other metabolites include N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. After immediate-release venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively. Following the administration of venlafaxine prolonged-release form, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. When equal daily doses of venlafaxine are administered as either an immediate-release tablet or prolonged-release form, the prolonged-release form provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release form. Food does not affect the bioavailability of venlafaxine and ODV. Venlafaxine is 27% and ODV 30% bound to plasma proteins. The mean elimination half-life of venlafaxine and ODV is about 5 and 11 hours, respectively. Venlafaxine is excreted mainly in the urine, mainly in the form of metabolites, either free or in conjugated form; about 2% is excreted in the faeces.