Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
Department of Pathology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.
J Pharm Biomed Anal. 2023 Sep 5;233:115439. doi: 10.1016/j.jpba.2023.115439. Epub 2023 May 3.
Recent studies presented the crucial role of montelukast (MON, a leukotriene receptor antagonist) against gouty arthritis and its protective effect on drug-induced liver and kidney injury. Allopurinol (ALO, a selective xanthine oxidase inhibitor) is also used for treatment of hyperuricemia, however, it induces hepatotoxicity and acute kidney injury. Therefore, this study introduces the first analytical/biochemical/histopathological assay for MON-ALO co-therapy and aims to: inspect the hepatic and renal impacts of ALO, MON and their combination in rats via biochemical and histopathological examinations, propose and validate a facile HPTLC method for concurrent estimation of ALO-MON binary mixture in human plasma, and employ this method to attain the targeted drugs in real rat plasma. First, the cited drugs in human plasma were simultaneously separated utilizing silica gel G 60 F-TLC plates. The separated bands were scanned at 268 nm demonstrating appropriate linearities (50.0-2000.0 ng band for each drug) and correlations (0.9986 and 0.9992 for ALO and MON, correspondingly). The calculated detection and quantitation limits, as well as recoveries confirmed the method's reliability. This procedure was validated, and the stability studies were achieved according to Bioanalytical Method Validation Guideline. This work was extended to investigate the possible hepatic and renal effects of ALO, MON and their co-therapy in rats. Using rat's gastric tube, the following was administered to four groups of male Wistar rats: Group Ia and Ib as control (received either saline or DMSO), Groups II, III, and IV were given MON, ALO, and MON+ALO, respectively. Good correlation between the measured biochemical parameters and the observed histopathological changes was encountered. Considerable drop in aspartate transaminase and alanine transaminase levels, in addition to lower liver damage changes were observed in the combination group compared to MON or ALO-treated groups. Regarding renal changes, ALO-MON co-therapy caused elevation in the serum creatinine and blood urea nitrogen levels when compared to controls and MON- or ALO-treated groups. Severe proteinaceous casts accumulation in kidney tubular lumen, severe congestion, and severe tubular necrosis were also noticed in the combination group. Lastly, this study suggests ALO-MON co-treatment not only as a preventive therapy against gouty arthritis but also as a new line to minimize ALO-induced hepatic injury. However, co-administration of ALO and MON should be further studied to assess the benefits and risks in various tissues, adjust the MON dosing, and monitor its nephrotoxic effect.
最近的研究表明，孟鲁司特（MON，白三烯受体拮抗剂）在痛风性关节炎中的关键作用及其对药物性肝损伤和肾损伤的保护作用。别嘌醇（ALO，一种选择性黄嘌呤氧化酶抑制剂）也用于治疗高尿酸血症，但其会引起肝毒性和急性肾损伤。因此，本研究首次介绍了 MON-ALO 联合治疗的分析/生化/组织病理学检测，并旨在：通过生化和组织病理学检查，检测 ALO、MON 及其组合对大鼠的肝肾功能的影响；提出并验证一种在人血浆中同时评估 ALO-MON 二元混合物的简便 HPTLC 方法，并采用该方法在实际大鼠血浆中获得目标药物。首先，在硅胶 G 60 F-TLC 板上同时分离人血浆中的参考药物。分离的条带在 268nm 处扫描，显示出适当的线性（每个药物的 50.0-2000.0ng 条带）和相关性（ALO 和 MON 分别为 0.9986 和 0.9992）。计算的检测限和定量限以及回收率证实了该方法的可靠性。该方法已得到验证，并根据生物分析方法验证指南进行了稳定性研究。本工作扩展到研究 ALO、MON 及其联合治疗在大鼠中的潜在肝肾功能影响。通过大鼠胃管，给四组雄性 Wistar 大鼠分别给予以下物质：第 Ia 和 Ib 组为对照组（分别给予生理盐水或 DMSO）；第 II、III 和 IV 组分别给予 MON、ALO 和 MON+ALO。观察到测量的生化参数与观察到的组织病理学变化之间存在良好的相关性。与 MON 或 ALO 治疗组相比，联合组的天门冬氨酸转氨酶和丙氨酸转氨酶水平显著下降，肝损伤变化也较小。关于肾脏变化，与对照组和 MON 或 ALO 治疗组相比，ALO-MON 联合治疗会导致血清肌酐和血尿素氮水平升高。在联合组中还观察到肾管状腔中大量蛋白质状铸型积聚、严重充血和严重肾小管坏死。最后，本研究表明，ALO-MON 联合治疗不仅可以作为痛风性关节炎的预防性治疗，还可以作为减轻 ALO 诱导的肝损伤的新方法。然而，还需要进一步研究 ALO 和 MON 的联合给药，以评估其在各种组织中的益处和风险，调整 MON 的剂量，并监测其肾毒性作用。
