Investigation of Pharmacokinetic and Pharmacodynamic Interactions between Citalopram and Duloxetine: An Integrated Analytical, Computational, Behavioral, and Biochemical Approach

Despite the prevalent utilization of antidepressant combinations in clinical settings, concerns persist regarding heightened side effects and potential drug–drug interactions (DDI). In response, this study investigates the interaction between citalopram (CIT) and duloxetine (DUL) using a multifaceted approach encompassing analytical, computational, behavioral, and biochemical techniques. Notably, the absence of published analytical methods tailored for studying antidepressant interactions underscores the novelty of our endeavor. We present the development and validation of a robust and sensitive assay, coupling liquid chromatography-tandem mass spectrometry. This method facilitates the simultaneous determination of DUL, a serotonin-norepinephrine reuptake inhibitor (SNRI), and CIT, a selective serotonin reuptake inhibitor (SSRI), in rat plasma following oral administration. Successful pharmacokinetic and DDI monitoring of DUL and CIT in rat plasma post a single oral dose of 120 mg/kg is achieved using this method. Our findings reveal DUL's influence on CIT's pharmacokinetic parameters, resulting in an increased area under the concentration–time curve (AUC) by 4-fold, peak plasma concentrations (Cmax) by 20-fold, maximum plasma concentration–time (Tmax) by 4-fold, and oral clearance (Cl/F) of CIT by 1.3-fold upon coadministration. Furthermore, our investigation explores the behavioral and biochemical ramifications of coadministering CIT and DUL through the sucrose preference test (SPT), forced swimming test (FST), and enzyme-linked immunosorbent assay (ELISA). We observe potential exacerbation of serotonin concentration and serotonin syndrome in rat models. Molecular modeling studies indicate that DUL may competitively inhibit CYP2D6, the principal enzyme responsible for CIT metabolism, as well as P-glycoprotein (P-gp), which extrudes CIT back to the intestinal lumen. These findings emphasize the imperative of further research into potential DDIs in psychiatric patients undergoing chronic treatment with DUL and CIT to mitigate adverse effects and serotonin syndrome.