title: Bioavailability, tissue distribution, and excretion characteristics of the novel carbonic anhydrase inhibitor tolsultazolamide in rats.
abstract: OBJECTIVE
  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%).
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Jin-da
authors: JD
authors: Wang
authors: 1] Thadweik Academy of Medicine, Beijing 100039, China [2] NhwaThad Pharmaceutical Co, Ltd, Xuzhou 221007, China.
authors: Yong-ping
authors: YP
authors: Shi
authors: Thadweik Academy of Medicine, Beijing 100039, China.
authors: Jing
authors: J
authors: Yin
authors: Institute of Health and Environmental Medicine, Academy of Military Medical Science, Beijing 100850, China.
authors: Zhi-yuan
authors: ZY
authors: Pan
authors: Institute of Health and Environmental Medicine, Academy of Military Medical Science, Beijing 100850, China.
authors: Wen-yu
authors: WY
authors: Cui
authors: Institute of Health and Environmental Medicine, Academy of Military Medical Science, Beijing 100850, China.
authors: Yan-fang
authors: YF
authors: Zhang
authors: Institute of Health and Environmental Medicine, Academy of Military Medical Science, Beijing 100850, China.
authors: Hai
authors: H
authors: Wang
mesh_terms: D000818:Animals; D001682:Biological Availability; D002257:Carbonic Anhydrase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D005260:Female; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases