K H Skelton1, C B Nemeroff, M J Owens. 1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
Abstract
RATIONALE: Benzodiazepines are effective in the treatment of anxiety disorders over a prolonged period of time. This results in relatively stable plasma concentrations over the course of a day. However, due to differences in drug clearance in rats, which generally metabolize and clear drugs much more rapidly than humans, it is difficult to model this steady level in rats. OBJECTIVES: Several methods of chronic alprazolam administration were compared to determine which would best result in reproducible, therapeutically relevant levels of the drug. METHODS: Male Sprague-Dawley rats were administered alprazolam via two subcutaneous routes, Alzet 2ML2 osmotic minipumps and commercially produced slow-release pellets, for 1 week and 2 weeks, respectively. Additionally, alprazolam was orally administered for 2 weeks by mixing the compound into a commercially available liquid, fat emulsion-based diet. The use of silastic implants to deliver several different benzodiazepines was also evaluated in vitro. RESULTS: Following 7 days of alprazolam administration at 2 mg/kg per day via osmotic minipump, plasma concentrations in ten identically treated rats ranged from <1 ng/ml to 97 ng/ml. Slow-release pellets produced more consistent plasma concentrations, but were only minimally effective at raising plasma concentrations. In vitro studies utilizing silastic implants containing 90 mg drug in 6 cm of tubing revealed stable release of only 45-55 microg/day alprazolam versus 625-650 microg/day diazepam. In contrast to these methodologies, incorporation of alprazolam into a commercially available liquid diet (approximately 25-150 mg/kg per day) provided consistent, dose-dependent increases in plasma concentrations of alprazolam and its metabolites in a range appropriate for mimicking clinical exposure. CONCLUSIONS: These findings indicate that the most effective technique to produce plasma concentrations of alprazolam that are reproducible, clinically pertinent, and consistent between rats is to incorporate the drug into a liquid diet. These findings may also be of value in determining dosing routes for other benzodiazepines or psychotropic drugs.
RATIONALE: Benzodiazepines are effective in the treatment of anxiety disorders over a prolonged period of time. This results in relatively stable plasma concentrations over the course of a day. However, due to differences in drug clearance in rats, which generally metabolize and clear drugs much more rapidly than humans, it is difficult to model this steady level in rats. OBJECTIVES: Several methods of chronic alprazolam administration were compared to determine which would best result in reproducible, therapeutically relevant levels of the drug. METHODS: Male Sprague-Dawley rats were administered alprazolam via two subcutaneous routes, Alzet 2ML2 osmotic minipumps and commercially produced slow-release pellets, for 1 week and 2 weeks, respectively. Additionally, alprazolam was orally administered for 2 weeks by mixing the compound into a commercially available liquid, fat emulsion-based diet. The use of silastic implants to deliver several different benzodiazepines was also evaluated in vitro. RESULTS: Following 7 days of alprazolam administration at 2 mg/kg per day via osmotic minipump, plasma concentrations in ten identically treated rats ranged from <1 ng/ml to 97 ng/ml. Slow-release pellets produced more consistent plasma concentrations, but were only minimally effective at raising plasma concentrations. In vitro studies utilizing silastic implants containing 90 mg drug in 6 cm of tubing revealed stable release of only 45-55 microg/day alprazolam versus 625-650 microg/day diazepam. In contrast to these methodologies, incorporation of alprazolam into a commercially available liquid diet (approximately 25-150 mg/kg per day) provided consistent, dose-dependent increases in plasma concentrations of alprazolam and its metabolites in a range appropriate for mimicking clinical exposure. CONCLUSIONS: These findings indicate that the most effective technique to produce plasma concentrations of alprazolam that are reproducible, clinically pertinent, and consistent between rats is to incorporate the drug into a liquid diet. These findings may also be of value in determining dosing routes for other benzodiazepines or psychotropic drugs.