新型碳酸酐酶抑制剂托西酸唑胺在大鼠体内的生物利用度、组织分布和排泄特征。
Bioavailability, tissue distribution, and excretion characteristics of the novel carbonic anhydrase inhibitor tolsultazolamide in rats.
机构信息
1] Institute of Health and Environmental Medicine, Academy of Military Medical Science, Beijing 100850, China [2] Thadweik Academy of Medicine, Beijing 100039, China [3] NhwaThad Pharmaceutical Co, Ltd, Xuzhou 221007, China.
1] Thadweik Academy of Medicine, Beijing 100039, China [2] NhwaThad Pharmaceutical Co, Ltd, Xuzhou 221007, China.
出版信息
Acta Pharmacol Sin. 2014 Feb;35(2):275-82. doi: 10.1038/aps.2013.146. Epub 2013 Dec 16.
AIM
Tolsultazolamide, a novel carbonic anhydrase inhibitor, is designed for the prophylaxis and treatment of acute mountain sickness. The aim of this study was to investigate the pharmacokinetics, tissue distribution, and excretion characteristics of tolsultazolamide and the sex difference in pharmacokinetics in rats.
METHODS
For pharmacokinetic study, rats were intravenously injected tolsultazolamide at 1 and 2 mg/kg or orally administered tolsultazolamide at 20, 40, or 80 mg/kg) in a pharmacokinetic study. The concentrations of tolsultazolamide in plasma were determined with high-performance liquid chromatography, with a liquid-liquid extraction. For tissue distribution study, tolsultazolamide (80 mg/kg) was orally administered to overnight fasted rats (six per group and three per sex). Samples were collected from the brain, heart, lung, liver, spleen, muscle, kidney, stomach, fat, intestines, pancreas and sexual gland. For excretion study, tolsultazolamide (40 mg/kg) was orally administered to 6 rats (three per sex). The urine, feces, and bile samples were collected at 24, 48, and 72 h.
RESULTS
After its intravenous administration, tolsultazolamide was rapidly eliminated from the plasma, with T1/2 of about 60-90 min. The AUC0-t and the initial concentration (C0) values were proportional to the intravenous doses. After its oral administration, tolsultazolamide showed dose-independent pharmacokinetic characteristics, with Tmax and T1/2 of approximately 2 h and 5-7 h, respectively, and good oral absolute bioavailability of about 60%. Tolsultazolamide was distributed widely in various tissues. The highest tolsultazolamide levels were detected in the stomach, intestine, spleen, lung, and kidney. Total excretion of unchanged tolsultazolamide in the urine, feces, and bile was less than 2%. The Cmax and AUC of tolsultazolamide were significantly higher in female rats than those in male rats. Clearance and volume of distribution were greater in male rats than those in female rats. The oral absolute bioavailability was also significantly different between female rats (about 83%) and male rats (about 37%).
CONCLUSION
Tolsultazolamide was well absorbed and widely distributed in the rat, and very little of the unchanged form was excreted. Sex had a significant effect on the pharmacokinetics of tolsultazolamide.
目的
托索唑胺是一种新型碳酸酐酶抑制剂，旨在预防和治疗急性高原病。本研究旨在研究托索唑胺在大鼠体内的药代动力学、组织分布和排泄特征，以及性别对药代动力学的影响。
方法
在药代动力学研究中，大鼠分别以 1 和 2mg/kg 静脉注射托索唑胺，或 20、40 或 80mg/kg 口服托索唑胺。采用高效液相色谱法，液-液萃取法测定血浆中托索唑胺的浓度。在组织分布研究中，大鼠禁食过夜后（每组 6 只，雌雄各 3 只）口服给予托索唑胺（80mg/kg）。从脑、心、肺、肝、脾、肌肉、肾、胃、脂肪、肠、胰腺和性器官中采集样品。在排泄研究中，大鼠（雌雄各 3 只）口服给予托索唑胺（40mg/kg）。在 24、48 和 72 小时收集尿液、粪便和胆汁样本。
结果
静脉注射后，托索唑胺迅速从血浆中消除，T1/2 约为 60-90 分钟。AUC0-t 和初始浓度（C0）值与静脉剂量成正比。口服给药后，托索唑胺表现出剂量依赖性的药代动力学特征，Tmax 和 T1/2 约为 2 小时和 5-7 小时，口服绝对生物利用度约为 60%。托索唑胺在各种组织中分布广泛。胃、肠、脾、肺和肾中托索唑胺水平最高。尿液、粪便和胆汁中未改变的托索唑胺总排泄量不到 2%。雌鼠的 Cmax 和 AUC 明显高于雄鼠。雌鼠的清除率和分布容积大于雄鼠，雌鼠的口服绝对生物利用度也明显高于雄鼠（约 83%对约 37%）。
结论
托索唑胺在大鼠体内吸收良好，分布广泛，原形排泄量很少。性别对托索唑胺的药代动力学有显著影响。
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