Original Article

Bioavailability, tissue distribution, and excretion characteristics of the novel carbonic anhydrase inhibitor tolsultazolamide in rats

Jin-da Wang, Yong-ping Shi, Jing Yin, Zhi-yuan Pan, Wen-yu Cui, Yan-fang Zhang, Hai Wang
DOI: 10.1038/aps.2013.146


Jin-da WANG1, 2, 3, Yong-ping SHI2, 3, Jing YIN2, Zhi-yuan PAN1, Wen-yu CUI1, Yan-fang ZHANG1, Hai WANG1, *
1Institute of Health and Environmental Medicine, Academy of Military Medical Science, Beijing 100850, China; 2Thadweik Academy of Medicine, Beijing 100039, China; 3NhwaThad Pharmaceutical Co, Ltd, Xuzhou 221007, China

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, and72 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.

Keywords: carbonic anhydrase inhibitors; tolsultazolamide; pharmacokinetics; tissue distribution; excretion; sex difference

This work was supported by grant from the State Key Project of Drug Research and Development of China (Grant No 2012ZX09J12109–01B).
* To whom correspondence should be addressed.
E-mail wh9588@sina.com
Received 2013-05-18 Accepted 2013-09-09

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