Elgawish Mohamed S, Atta Asmaa M, Hafeez Sameh M, Abdel Mageed Sherif S, Mahmoud Abdulla M A, Moustafa Moftah A, Ali Mohamed A
Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
Chemistry Department, Korea University, Seoul 02841, Korea Republic.
ACS Pharmacol Transl Sci. 2024 Nov 9;7(12):4032-4042. doi: 10.1021/acsptsci.4c00506. eCollection 2024 Dec 13.
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 ( ) by 20-fold, maximum plasma concentration-time ( ) 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.
尽管抗抑郁药联合使用在临床环境中普遍存在，但对于副作用增加和潜在药物相互作用（DDI）的担忧仍然存在。作为回应，本研究采用多方面的方法，包括分析、计算、行为和生化技术，研究西酞普兰（CIT）和度洛西汀（DUL）之间的相互作用。值得注意的是，缺乏专门用于研究抗抑郁药相互作用的已发表分析方法凸显了我们这项工作的新颖性。我们展示了一种结合液相色谱 - 串联质谱的强大而灵敏的检测方法的开发与验证。该方法有助于在口服给药后同时测定大鼠血浆中的度洛西汀（一种5-羟色胺 - 去甲肾上腺素再摄取抑制剂（SNRI））和西酞普兰（一种选择性5-羟色胺再摄取抑制剂（SSRI））。使用该方法成功实现了对大鼠单次口服120mg/kg剂量后血浆中度洛西汀和西酞普兰的药代动力学及DDI监测。我们的研究结果显示度洛西汀对西酞普兰药代动力学参数有影响，联合给药时西酞普兰的浓度 - 时间曲线下面积（AUC）增加4倍，血浆峰浓度（ ）增加20倍，最大血浆浓度 - 时间（ ）增加4倍，口服清除率（Cl/F）增加1.3倍。此外，我们的研究通过蔗糖偏好试验（SPT）、强迫游泳试验（FST）和酶联免疫吸附测定（ELISA）探索了联合给予西酞普兰和度洛西汀的行为和生化影响。我们在大鼠模型中观察到5-羟色胺浓度和5-羟色胺综合征有潜在加重。分子建模研究表明，度洛西汀可能竞争性抑制负责西酞普兰代谢的主要酶CYP2D6以及将西酞普兰挤出回到肠腔的P-糖蛋白（P-gp）。这些发现强调了对接受度洛西汀和西酞普兰长期治疗的精神科患者潜在DDI进行进一步研究以减轻不良反应和5-羟色胺综合征的必要性。
