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

Rationale: Benzodiazepines are effective in the treatment of anxiety disord ers over a prolonged period of time. This results in relatively stable plas ma concentrations over the course of a day. However, due to differences in drug clearance in rats, which generally metabolize and clear drugs much mor e rapidly than humans, it is difficult to model this steady level in rats. Objectives: Several methods of chronic alprazolam administration were compa red to determine which would best result in reproducible, therapeutically r elevant levels of the drug. Methods: Male Sprague-Dawley rats were administ ered alprazolam via two subcutaneous routes, Alzet 2ML2 osmotic minipumps a nd commercially produced slow-release pellets, for 1 week and 2 weeks, resp ectively. Additionally, alprazolam was orally administered for 2 weeks by m ixing the compound into a commercially available liquid, fat emulsion-based diet. The use of silastic implants to deliver several different benzodiaze pines was also evaluated in vitro. Results: Following 7 days of alprazolam administration at 2 mg/kg per day via osmotic minipump, plasma concentratio ns in ten identically treated rats ranged from <1 ng/ml to 97 ng/ml. Slow-r elease pellets produced more consistent plasma concentrations, but were onl y minimally effective at raising plasma concentrations. In vitro studies ut ilizing silastic implants containing 90 mg drug in 6 cm of tubing revealed stable release of only 45-55 mu g/day alprazolam versus 625-650 mu g/day di azepam. Tn contrast to these methodologies, incorporation of alprazolam int o a commercially available liquid diet (similar to 25-150 mg/kg per day) pr ovided consistent, dose-dependent increases in plasma concentrations of alp razolam and its metabolites in a range appropriate for mimicking clinical e xposure. Conclusions: These findings indicate that the most effective techn ique to produce plasma concentrations of alprazolam that are reproducible, clinically pertinent, and consistent between rats is to incorporate the dru g into a liquid diet. These findings may also be of value in determining do sing routes for other benzodiazepines or psychotropic drugs.