Zentner Isaac, Back Hyun-Moon, Kagan Leonid, Subbian Selvakumar, Nagajyothi Jyothi, Srivastava Shashikant, Pasipanodya Jotam, Gumbo Tawanda, Bisson Gregory P, Vinnard Christopher
Public Health Research Institute, New Jersey Medical School, Newark, NJ, United States.
Department of Pharmaceutics and Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.
Front Pharmacol. 2020 Jul 29;11:1103. doi: 10.3389/fphar.2020.01103. eCollection 2020.
The potential for hepatotoxicity during isoniazid-based tuberculosis (TB) treatment presents a major challenge for TB control programs worldwide. We sought to determine whether pharmacokinetic exposures of isoniazid and its metabolites were related to cellular oxidation/reduction status and downstream markers of oxidative DNA damage.
We performed intensive pharmacokinetic sampling among isoniazid-treated patients to determine the relative plasma exposures of isoniazid, acetylisoniazid, hydrazine, and acetylhydrazine. Physiologically-based pharmacokinetic modeling was used to estimate liver tissue exposures during a 24-h dosing interval for each compound. We experimentally treated HepG2 cells with isoniazid and metabolites at equimolar concentrations corresponding to these exposures for 7, 14, and 28-day periods, and performed assays related to redox imbalance and oxidative DNA damage at each timepoint. We related a urine marker of oxidative DNA damage to serum isoniazid pharmacokinetic exposures and pharmacogenetics in a clinical study.
Among isoniazid-treated patients, serum concentrations of hydrazine and isoniazid concentrations were highly correlated. At equimolar concentrations that approximated hepatic tissue exposures during a 24-h dosing interval, hydrazine demonstrated the highest levels of redox imbalance, mitochondrial injury, and oxidative DNA damage over a 28-day treatment period. In a clinical validation study of isoniazid-treated TB patients, peak isoniazid serum concentrations were positively associated with a urine biomarker of oxidative DNA damage.
Isoniazid and its metabolites share the potential for oxidative cellular damage, with the greatest effects observed for hydrazine. Future studies should investigate the clinical consequences of oxidative stress with regards to clinical episodes of drug induced liver injury during isoniazid treatment.
基于异烟肼的结核病治疗过程中出现肝毒性的可能性给全球结核病控制项目带来了重大挑战。我们试图确定异烟肼及其代谢产物的药代动力学暴露是否与细胞氧化/还原状态以及氧化性DNA损伤的下游标志物有关。
我们对接受异烟肼治疗的患者进行了密集的药代动力学采样，以确定异烟肼、乙酰异烟肼、肼和乙酰肼的相对血浆暴露量。基于生理的药代动力学模型用于估计每种化合物在24小时给药间隔期间的肝组织暴露量。我们用与这些暴露量相当的等摩尔浓度的异烟肼和代谢产物对HepG2细胞进行了7天、14天和28天的实验处理，并在每个时间点进行了与氧化还原失衡和氧化性DNA损伤相关的检测。在一项临床研究中，我们将氧化性DNA损伤的尿液标志物与血清异烟肼药代动力学暴露和药物遗传学相关联。
在接受异烟肼治疗的患者中，肼的血清浓度与异烟肼浓度高度相关。在24小时给药间隔期间接近肝组织暴露量的等摩尔浓度下，在28天的治疗期内，肼表现出最高水平的氧化还原失衡、线粒体损伤和氧化性DNA损伤。在一项异烟肼治疗的结核病患者的临床验证研究中，异烟肼血清峰值浓度与氧化性DNA损伤的尿液生物标志物呈正相关。
异烟肼及其代谢产物具有造成细胞氧化损伤的可能性，其中肼的影响最大。未来的研究应调查氧化应激在异烟肼治疗期间药物性肝损伤临床发作方面的临床后果。
