Department of Rheumatology of the First Hospital and Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410007, Hunan, China.
Shenzhen Institute for Drug Control, Shenzhen, 518057, Guangdong, China.
Arch Toxicol. 2022 Dec;96(12):3245-3255. doi: 10.1007/s00204-022-03368-1. Epub 2022 Aug 30.
Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum (Thunb.) Rehd. et Wils which exhibits significant analgesic, anti-inflammatory, and immunosuppressive effects. Sinomenine hydrochloride (SH) preparations, classified as natural disease-modifying antirheumatic drugs, are currently available for the treatment of rheumatoid arthritis and other rheumatic diseases. Our toxicity evaluation demonstrated that the median lethal dose of SH in female Sprague-Dawley (SD) rats was over 11 times greater than that in male SD rats, revealing striking sex-linked differences in the safety profile of SH. The present study was designed to investigate differences in the pharmacokinetics (PKs) and tissue distribution of SH between male and female SD rats after a single oral dose of 25 mg/kg. PK and tissue distribution studies were performed using a validated UPLC-MS/MS method. The results showed that SH-treated SD female rats displayed markedly greater drug exposure, and SH exhibited a longer half-life and slower clearance rate than comparable studies in male rats. Moreover, the tissue distribution study confirmed that the sinomenine concentration in female rats was considerably greater in the internal organs than in male rats. Our study demonstrates, for the first time, significant sex-related differences in the safety profile and PKs of SH, which may be associated with a distinct sex-dependent metabolic mechanism of sinomenine.
青藤碱是从中国药用植物青风藤（Thunb.）Rehd. et Wils 中分离得到的一种具有生物活性的生物碱，具有显著的镇痛、抗炎和免疫抑制作用。盐酸青藤碱（SH）制剂被归类为天然疾病修饰抗风湿药物，目前可用于治疗类风湿关节炎和其他风湿性疾病。我们的毒性评估表明，SH 在雌性 Sprague-Dawley（SD）大鼠中的半数致死剂量（LD50）是雄性 SD 大鼠的 11 倍以上，表明 SH 的安全性特征存在明显的性别差异。本研究旨在研究雄性和雌性 SD 大鼠单次口服 25mg/kg 剂量后 SH 的药代动力学（PK）和组织分布差异。PK 和组织分布研究使用了经过验证的 UPLC-MS/MS 方法。结果表明，SH 处理的雌性 SD 大鼠的药物暴露明显增加，SH 的半衰期更长，清除率更慢，与雄性大鼠的可比研究相比。此外，组织分布研究证实，雌性大鼠的内部器官中青藤碱的浓度明显高于雄性大鼠。本研究首次证明了 SH 在安全性和 PK 方面存在显著的性别差异，这可能与青藤碱的性别依赖性代谢机制有关。
