The combined therapy benefits of losartan and rosuvastatin, within the vascular injury, have been well characterized. Nonetheless, the pharmacokinetic interactions between such therapeutic agents have not been yet figured out, making the need for a sensitive analytical technique to be of great significance. In view of this, a highly selective, sensitive, and well-validated liquid chromatography–tandem mass spectrometric technique has been developed for the simultaneous estimation of losartan (LOS) and rosuvastatin (ROS) within the rat plasma using simvastatin as an internal standard. The proposed technique adopted a simple plasma protein preparation by acetonitrile for the extraction and purification of the drug-plasma samples obtained from the rat animal models. A separation process on the Agilent™ Eclipse-Plus® (C18, 0.46 × 15 cm, 3.5 μm) columns was conducted using gradient mobile phase system comprising of water/0.1%w/v formic acid and acetonitrile at 0.9 mL min−1 flow rate. Precursor quantification into production was performed using the multiple reaction monitoring within the positive-ionization mode. Method linearity was obeyed within 1–5000 ng mL−1 for both LOS and ROS, while the validation process was performed according to the guidelines adopted by the US-FDA bioanalytical framework. The pharmacokinetic interactions after oral co-administration of both drugs furnished significant changes within their respective pharmacokinetic parameters including peak-plasma concentration, elimination t1/2, AUC, volume of distribution, and plasma clearance. Additionally, a mutual competitive displacement for each drug from their plasma albumin bindings showed a significant impact on drug's pharmacokinetic profile and was demonstrated through molecular modeling investigations. Finally, the presented study laid an evidence for a two-way pharmacological synergism with the combined therapy of LOS and ROS via increased hepatic influx of ROS and peak-plasma concentration of EXP3174, the LOS more potent metabolite. Therefore, the proposed method provides a useful tool for the drug–drug interaction investigations being valuable for prospective bioequivalence studies and therapeutic drug monitoring.

中文翻译：

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使用液相色谱-串联质谱技术同时测定大鼠血浆中氯沙坦和瑞舒伐他汀在药代动力学和药物相互作用研究中的应用

氯沙坦和瑞舒伐他汀在血管损伤中的联合治疗益处已得到充分表征。尽管如此，这些治疗剂之间的药代动力学相互作用尚未弄清楚，因此需要一种灵敏的分析技术具有重要意义。鉴于此，开发了一种高选择性、灵敏且经过充分验证的液相色谱-串联质谱技术，用于使用辛伐他汀作为内标同时测定大鼠血浆中的氯沙坦 (LOS) 和罗苏伐他汀 (ROS)。所提出的技术采用简单的乙腈血浆蛋白制备方法来提取和纯化从大鼠动物模型中获得的药物血浆样品。Agilent™ Eclipse-Plus® (C18, 0.46 × 15 cm, 3. 5 μm) 柱使用梯度流动相系统进行，该系统包含水/0.1%w/v 甲酸和乙腈，流速为 0.9 mL min-1。在正电离模式下使用多反应监测对前体进行量化。LOS 和 ROS 的方法线性均在 1–5000 ng mL-1 范围内，而验证过程是根据 US-FDA 生物分析框架采用的指南进行的。两种药物口服共同给药后的药代动力学相互作用在其各自的药代动力学参数内发生了显着变化，包括血浆峰浓度、消除 t1/2、AUC、分布容积和血浆清除率。此外，每种药物与血浆白蛋白结合的相互竞争置换显示出对药物药代动力学特征的显着影响，并通过分子模型研究得到证实。最后，本研究为 LOS 和 ROS 联合治疗通过增加 ROS 的肝脏流入和 EXP3174 的血浆峰值浓度（LOS 更有效的代谢物）的双向药理学协同作用奠定了证据。因此，所提出的方法为药物-药物相互作用研究提供了有用的工具，对前瞻性生物等效性研究和治疗药物监测很有价值。本研究为 LOS 和 ROS 联合治疗通过增加 ROS 的肝脏流入和 EXP3174 的峰值血浆浓度（LOS 更有效的代谢物）的双向药理学协同作用奠定了证据。因此，所提出的方法为药物-药物相互作用研究提供了有用的工具，对前瞻性生物等效性研究和治疗药物监测很有价值。本研究为 LOS 和 ROS 联合治疗通过增加 ROS 的肝脏流入和 EXP3174 的峰值血浆浓度（LOS 更有效的代谢物）的双向药理学协同作用奠定了证据。因此，所提出的方法为药物-药物相互作用研究提供了有用的工具，对前瞻性生物等效性研究和治疗药物监测很有价值。