Tian Junjun, Lei Peng, He Yifei, Zhang Ning, Ge Xinyu, Luo Liqiang, Yan Shu, Diao Xingxing
Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, PR China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, PR China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, PR China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Sep 1;1181:122915. doi: 10.1016/j.jchromb.2021.122915.
3-n-Butylphthalide (NBP) has a considerable neuroprotective effect and is currently used for the treatment of ischemic stroke. NBP was launched on the market in 2004. However, information on its metabolism in humans and preclinical animal models is insufficient. Although the metabolism of unradiolabeled NBP in humans has been reported, the quantitative metabolite profile, blood-to-plasma radioactivity concentration ratio (B/P), and tissue distribution of this drug remain unclear. We evaluated the pharmacokinetics, tissue distribution, mass balance, and metabolism of NBP in rats after a single oral dose of 60 mg/kg (100 μCi/kg) [C]NBP to understand the biotransformation of NBP comprehensively and to provide preclinical drug metabolism data prior to human mass balance studies with [C]NBP in the near future. NBP absorption was rapid (T = 0.75 h) and declined with a terminal half-life of 9.73 h. In rats, the B/P was 0.63 during the 48 h postdose period, indicating that drug-related substances did not tend to be distributed into blood cells. Tissue distribution was determined by using the oxidative combustion method. NBP-related components were widely distributed throughout the body, and high concentrations were detected in the stomach, small intestine, fat, bladder, kidney, liver and ovary. At 168 h after oral administration, the mean cumulative recovered radioactivity was 99.85% of the original dose, and was 85.12% in urine and 14.73% in feces. Metabolite profiles were detected via radiochromatography. A total of 49 metabolites were identified in rat plasma, urine, and feces. The main metabolic pathways were oxidation, glucuronidation, and sulfation. Overall, NBP was absorbed rapidly, distributed throughout the body, and excreted in the form of metabolites. Urine was the main excretion route, and the absorption, distribution, metabolism and excretion of NBP showed no significant gender difference between male and female rats.
3-正丁基苯酞（NBP）具有显著的神经保护作用，目前用于治疗缺血性中风。NBP于2004年上市。然而，关于其在人体和临床前动物模型中的代谢信息不足。虽然已报道了未标记NBP在人体中的代谢情况，但该药物的定量代谢物谱、血药浓度与血浆放射性浓度比（B/P）以及组织分布仍不清楚。我们评估了大鼠单次口服60 mg/kg（100 μCi/kg）[C]NBP后的药代动力学、组织分布、质量平衡和代谢情况，以全面了解NBP的生物转化，并在不久的将来为人体[C]NBP质量平衡研究提供临床前药物代谢数据。NBP吸收迅速（T = 0.75 h），终末半衰期为9.73 h。在大鼠中，给药后48小时内B/P为0.63，表明药物相关物质不易分布到血细胞中。采用氧化燃烧法测定组织分布。NBP相关成分广泛分布于全身，在胃、小肠、脂肪、膀胱、肾脏、肝脏和卵巢中检测到高浓度。口服给药后168小时，平均累积回收放射性为原始剂量的99.85%，其中尿液中为85.12%，粪便中为14.73%。通过放射色谱法检测代谢物谱。在大鼠血浆、尿液和粪便中总共鉴定出49种代谢物。主要代谢途径为氧化反应、葡萄糖醛酸化反应和硫酸化反应。总体而言，NBP吸收迅速，分布于全身，并以代谢物形式排泄。尿液是主要排泄途径，NBP的吸收、分布、代谢和排泄在雄性和雌性大鼠之间无显著性别差异。
