Wu Wei, Cheng Rui, Boucetta Hamza, Xu Lei, Pan Jing-Ru, Song Min, Lu Yu-Ting, Hang Tai-Jun
Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, China.
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
Front Pharmacol. 2022 Jun 9;13:910923. doi: 10.3389/fphar.2022.910923. eCollection 2022.
Tripterygium glycosides tablets (TGT) are widely used for treating nephrotic syndrome (NS), but hepatotoxicity is frequently reported. The presence of underlying disease(s) can alter the disposition of drugs and affect their efficacy and toxicity. However, no studies have reported the impact of NS on the ADME profiles of TGT or its subsequent impact on the efficacy and toxicity. Thus, the efficacy and hepatotoxicity of TGT were evaluated in normal and NS rats after oral administration of TGT (10 mg/kg/day) for 4 weeks. The corresponding ADME profiles of the six key TGT components (triptolide (TPL), wilforlide A (WA), wilforgine (WFG), wilfortrine (WFT), wilfordine (WFD), and wilforine (WFR)) were also measured and compared in normal and NS rats after a single oral gavage of 10 mg/kg TGT. Canonical correlation analysis (CCA) of the severity of NS and the exposure of the six key TGT components was performed to screen the anti-NS and hepatotoxic material bases of TGT. Finally, the efficacy and hepatotoxicity of the target compounds were evaluated . The results showed that TGT decreased the NS symptoms in rats, but caused worse hepatotoxicity under the NS state. Significant differences in the ADME profiles of the six key TGT components between the normal and NS rats were as follows: higher plasma and tissue exposure, lower urinary and biliary excretion, and higher fecal excretion for NS rats. Based on CCA and verification, TPL, WA, WFG, WFT, WFD, and WFR were identified as the anti-NS material bases of TGT, whereas TPL, WFG, WFT, and WFD were recognized as the hepatotoxic material bases. In conclusion, NS significantly altered the ADME profiles of the six key TGT components detected in rats, which were related to the anti-NS and hepatotoxic effects of TGT. These results are useful for the rational clinical applications of TGT.
雷公藤多苷片（TGT）被广泛用于治疗肾病综合征（NS），但肝毒性报道屡见不鲜。基础疾病的存在可改变药物的处置过程，并影响其疗效和毒性。然而，尚无研究报道NS对TGT药动学特征的影响及其对疗效和毒性的后续作用。因此，在正常大鼠和NS大鼠中口服给予TGT（10mg/kg/天）4周后，评估TGT的疗效和肝毒性。在正常大鼠和NS大鼠单次口服灌胃10mg/kg TGT后，还测定并比较了TGT六种关键成分（雷公藤甲素（TPL）、卫矛醇A（WA）、雷公藤吉碱（WFG）、雷公藤春碱（WFT）、雷公藤定碱（WFD）和雷公藤宁碱（WFR））相应的药动学特征。对NS严重程度与TGT六种关键成分暴露量进行典型相关分析（CCA），以筛选TGT抗NS和肝毒性物质基础。最后，评估目标化合物的疗效和肝毒性。结果显示，TGT可减轻大鼠NS症状，但在NS状态下会导致更严重的肝毒性。正常大鼠与NS大鼠之间，TGT六种关键成分的药动学特征存在显著差异：NS大鼠血浆和组织暴露量更高，尿液和胆汁排泄量更低，粪便排泄量更高。基于CCA及验证，TPL、WA、WFG、WFT、WFD和WFR被确定为TGT抗NS物质基础，而TPL、WFG、WFT和WFD被认为是肝毒性物质基础。总之，NS显著改变了大鼠体内检测到的TGT六种关键成分的药动学特征，这与TGT的抗NS和肝毒性作用相关。这些结果有助于TGT的合理临床应用。
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