Apalife 10/Apalife 15 Mechanism of Action

Pharmacology: It has been proposed that Aripiprazole's efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D₂ and serotonin 5HT_1a receptors and antagonism of serotonin 5HT_2a receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D₂ and D₃, serotonin 5HT_1a and 5HT_2a receptors and moderate affinity for dopamine D₄, serotonin 5HT_2c and 5HT₇, alpha-1 adrenergic and histamine H₁ receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of Aripiprazole.
Pharmacokinetics: Absorption: Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of Aripiprazole.
Distribution: Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, Aripiprazole and dehydro-Aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.
Biotransformation: Aripiprazole is extensively metabolized by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of Aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-Aripiprazole, the active metabolite, represents about 40% of Aripiprazole AUC in plasma.
Elimination: The mean elimination half-lives for Aripiprazole are approximately 75 hours in extensive metabolizers of CYP2D6 and approximately 146 hours in poor metabolizers of CYP2D6. The total body clearance of Aripiprazole is 0.7 mL/min/kg, which is primarily hepatic. Following a single oral dose of [¹⁴C]-labelled Aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the feces. Less than 1% of unchanged Aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the feces.