The long-course treatment of tuberculosis with isoniazid (INH) leads to hazardous side effects on liver and poor patient compliance. To overcome these toxic effects caused by INH, a unique hepatoprotective co-drug platform was developed by tethering INH with ursodeoxycholic acid (UDCA) – an antioxidant bile acid for possible synergistic outcome. INH and UDCA were linked into co-drug (UI ) through a bioreversible amide linkage by EDCI coupling. UI resisted hydrolysis in acidic (pH 1.2) and basic (pH 7.4) buffers and stomach homogenate of rat, whereas exhibited significant hydrolysis (83.38%) in intestinal homogenate over a period of 6 h. The effect of UI in attenuating oxidative stress and reinstating the normal physiology of liver was striking as it restored the levels of glutathione peroxidase and superoxide dismutase enzymes to normal. Result obtained for antimycobacterial activity assessment clearly demonstrated that UI was as potent as INH in lowering the mycobacterial load in mice. The outcomes of this exploration confirm that the proposed prodrug can add safety as well as efficiency to future medical procedures of tuberculosis management.

中文翻译：

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异烟肼保肝胆汁酸联合药物：合成、动力学及抗分枝杆菌潜力研究

用异烟肼 (INH) 长期治疗结核病会导致对肝脏的有害副作用和患者依从性差。为了克服 INH 引起的这些毒性作用，通过将 INH 与熊去氧胆酸 (UDCA)（一种抗氧化胆汁酸）结合，可能产生协同结果，开发了一种独特的保肝联合药物平台。INH 和 UDCA 通过 EDCI 偶联通过生物可逆酰胺键连接成共药 (UI)。UI 在酸性 (pH 1.2) 和碱性 (pH 7.4) 缓冲液和大鼠胃匀浆中抵抗水解，而在肠匀浆中 6 小时内显示显着水解 (83.38%)。UI 在减轻氧化应激和恢复肝脏正常生理方面的作用是惊人的，因为它使谷胱甘肽过氧化物酶和超氧化物歧化酶的水平恢复到正常水平。获得的抗分枝杆菌活性评估结果清楚地表明，UI 在降低小鼠分枝杆菌负荷方面与 INH 一样有效。这项探索的结果证实，提议的前药可以为未来结核病管理的医疗程序增加安全性和效率。