Analysis of Pharmacokinetic and Pharmacodynamic Interactions Between Chlorpromazine and Risperidone via Simultaneous Measurement of Multiple Receptor Occupancy in the Rat Brain

<b>Background/Objectives:</b> Combination therapy for schizophrenia may exacerbate side effects mediated by multiple brain receptors. This study aimed to elucidate the pharmacodynamic and pharmacokinetic interactions between chlorpromazine and risperidone. We investigated dopamine 2 (D₂), serotonin 2A (5-HT_2A), histamine 1 (H₁), and muscarinic acetylcholine (mACh) receptor occupancy in the brain as well as pharmacokinetic interactions after oral administration of chlorpromazine and risperidone in rats. <b>Methods:</b> Rats were orally administered chlorpromazine, risperidone, or their combination. A tracer cocktail solution was injected intravenously to measure multiple receptor occupancies simultaneously. Tracer and drug concentrations in the brain tissue and plasma were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). <b>Results:</b> Receptor occupancy increased in a dose-dependent manner. The doses required for 70% D₂ receptor occupancy were 4.5 mg/kg for chlorpromazine and 1.5 mg/kg for risperidone. Co-administration of chlorpromazine (4.5 mg/kg) and risperidone (1.5 mg/kg) resulted in an increase in D₂ and 5-HT_2A receptor occupancy to approximately 90%. Risperidone alone caused a transient increase in H₁ receptor occupancy to 80%, while co-administration increased mACh receptor occupancy to 60%. Co-administration with chlorpromazine significantly increased the plasma concentrations of risperidone and its metabolite, paliperidone, and decreased the oral clearance of risperidone by 5.9-fold. <b>Conclusions:</b> Co-administration of chlorpromazine and risperidone increases the occupancy of D₂, 5-HT_2A, and mACh receptors in the rat brain and increases the plasma concentrations of risperidone and paliperidone, suggesting a potential risk of enhanced adverse effects due to both pharmacokinetic and pharmacodynamic interactions involving target and non-target brain receptors.