A comparison of plasma alprazolam concentrations following different routes of chronic administration in the Sprague-Dawley rat: implications for psychotropic drug research.

Abstract

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. Several methods of chronic alprazolam administration were compared to determine which would best result in reproducible, therapeutically relevant levels of the drug. 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. 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. 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.