Safety pharmacology of sibutramine mesylate, an anti-obesity drug

Hum Exp Toxicol. 2005 Mar;24(3):109-19. doi: 10.1191/0960327105ht510oa.

Abstract

Sibutramine mesylate is a new anti-obesity drug. It is a crystalline salt of sibutramine developed to improve the solubility of sibutramine hydrochloride. Methanesulfonic acid was used as a salt-forming acid instead of hydrochloric acid, resulting in a greatly improved solubility of 1000 mg/mL in water. Sibutramine mesylate was administered orally to ICR mice, Sprague-Dawley rats, and beagle dogs at dose levels of 1.15, 3.45, and 11.50 mg/kg to measure its effects on the central nervous system (CNS), general behaviour, cardiovascular-respiratory system and the other organ systems. Following administration of sibutramine mesylate, spontaneous locomotor activity was significantly increased from 120 min to 24 hours at 3.45 mg/kg and from 30 min to 24 hours at 11.50 mg/kg. Furthermore, there were a decrease in hexobarbital-induced sleep time, an increase in respiratory rate at 120 min, increases in intestinal transport capacity and gastric pH at 11.50 mg/kg, and decreases in gastric volume and total acidity at 3.45 and 11.50 mg/kg. However sibutramine mesylate caused no effects on general behaviour, motor coordination, body temperature, analgesia, convulsion, blood pressure, heart rate, electrocardiogram, cardiac functions of the isolated rat heart, isolated smooth muscles and renal function. Based on the above results, it was concluded that sibutramine mesylate caused effects on the spontaneous locomotor activity, hexobarbital-induced sleep time, respiration, gastrointestinal transport, and gastric secretion at a dose level of 3.45 mg/kg or greater but caused no effects on other general pharmacological reactions.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Obesity Agents / pharmacology*
  • Cyclobutanes / pharmacology*
  • Dogs
  • Dose-Response Relationship, Drug
  • Female
  • Gastric Mucosa / metabolism
  • Gastrointestinal Transit / drug effects
  • Guinea Pigs
  • Male
  • Mice
  • Mice, Inbred ICR
  • Motor Activity / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Respiration / drug effects
  • Sleep / drug effects

Substances

  • Anti-Obesity Agents
  • Cyclobutanes
  • sibutramine