Pharmacology: Mechanism of Action: The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that paliperidone's therapeutic activity in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2A) receptor antagonism.
Pharmacodynamics: Paliperidone palmitate is hydrolyzed to paliperidone. It is a centrally active dopamine D2 antagonist with predominant serotonergic 5-HT2A antagonistic activity. Paliperidone is also active as an antagonist at α1- and α2-adrenergic receptors and H1-histaminergic receptors. Paliperidone has no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers is qualitatively and quantitatively similar.
Pharmacokinetics: Due to its extremely low water solubility, paliperidone palmitate dissolves slowly after IM injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. Following a single IM dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentration (Cmax) at a median tmax of 13 days. The release of the drug starts as early as day 1 and lasts for as long as 126 days.
One week following administration of a single oral dose of immediate-release 14C-paliperidone 1 mg, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces.