Ahmad Aftab, Dhanalekshmi Unnikrishnan Meenakshi, Koumaravelu Kailasam, Francis Arul Prakash, Khan Shah Alam, Abuzinadah Mohammed F, Selvasudha Nandakumar
Health Information Technology Department, Faculty of Applied Studies, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Pharmacovigilance and Medication Safety Unit, Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Pharmaceuticals (Basel). 2023 Mar 1;16(3):380. doi: 10.3390/ph16030380.
A pharmaceutical formulation with favorable pharmacokinetic parameters is more likely to be efficacious and safe to overcome the failures of the drug resulting from lack of efficacy, poor bioavailability, and toxicity. In this view, we aimed to evaluate the pharmacokinetic functionalities and safety margin of an optimized CS-SS nanoformulation (F40) by in vitro/in vivo methods. The everted sac technique was used to evaluate the improved absorption of a simvastatin formulation. In vitro protein binding in bovine serum and mice plasma was performed. The formulation's liver and intestinal CYP3A4 activity and metabolic pathways were investigated by the qRT-PCR technique. The excretion of cholesterol and bile acids was measured to demonstrate the formulation's cholesterol depletion effect. Safety margins were determined by histopathology as well as fiber typing studies. In vitro protein binding results revealed the existence of a high percentage of free drugs (22.31 ± 3.1%, 18.20 ± 1.9%, and 16.9 ± 2.2%, respectively) compared to the standard formulation. The controlled metabolism in the liver was demonstrated from CYP3A4 activity. The formulation showed enhanced PK parameters in rabbits such as a lower C, clearance, and a higher T, AUC, V, and t. qRT-PCR screening further proved the different metabolic pathways followed by simvastatin (SREBP-2) and chitosan (PPAR-γ pathway) in the formulation. The results from qRT-PCR and histopathology confirmed the toxicity level. Hence, this pharmacokinetic profile of the nanoformulation proved it has a unique synergistic hypolipidemic modality.
具有良好药代动力学参数的药物制剂更有可能有效且安全，以克服因疗效不佳、生物利用度差和毒性导致的药物失效问题。基于此观点，我们旨在通过体外/体内方法评估优化后的CS-SS纳米制剂（F40）的药代动力学功能和安全边际。采用外翻肠囊技术评估辛伐他汀制剂的吸收改善情况。进行了牛血清和小鼠血浆中的体外蛋白结合实验。通过qRT-PCR技术研究了该制剂对肝脏和肠道CYP3A4活性及代谢途径的影响。测量胆固醇和胆汁酸的排泄以证明该制剂的胆固醇消耗作用。通过组织病理学以及纤维分型研究确定安全边际。体外蛋白结合结果显示，与标准制剂相比，游离药物的比例较高（分别为22.31±3.1%、18.20±1.9%和16.9±2.2%）。从CYP3A4活性可证明肝脏中的代谢受到控制。该制剂在兔体内显示出增强的药代动力学参数，如较低的C、清除率以及较高的T、AUC、V和t。qRT-PCR筛选进一步证明了制剂中辛伐他汀（SREBP-2途径）和壳聚糖（PPAR-γ途径）遵循不同的代谢途径。qRT-PCR和组织病理学结果证实了毒性水平。因此，该纳米制剂的这种药代动力学特征证明其具有独特的协同降血脂模式。
