EVALUATION OF A NOVEL NIMODIPINE DELIVERY SYSTEM IN CONSCIOUS RATS THAT ALLOWS SUSTAINED-RELEASE FOR 24 H

Methodologies that allow prolonged drug administration in animal model s, while minimizing surgery and anesthesia, are an important contribut ion towards studies in awake conditions. Commercially available drug d elivery systems like pellets can be customized for the evaluation of e xperimental therapies with minimal or no discomfort to animals. Our ob jective was to evaluate pharmacokinetic and physiologic parameters aft er subcutaneous implantation of rapid 24 h release nimodipine pellets in rats for their potential use as a delivery system for stroke therap eutics. A day prior to the study Sprague-Dawley rats were anesthetized (halothane, N2O, O-2) for femoral vessel cannulation and later return ed to their cages. On the day of the study the rats were briefly anest hetized (identical regimen as before), and assigned to two groups: nim odipine (NP) and placebo (PL). NP rats received either 0.5(n=4), 1(n=3 ), 2(n=2), 4(n=2), or 15(n=5) mg pellets (Innovative Research of Ameri ca Inc., Sarasota, FL, USA) and PL rats (n=5) received placebo pellets . Nimodipine plasma levels were measured at 1, 3, and 6 h. In addition , the 15 mg NP group was followed at 18 and 24 h. Immediately followin g decapitation the brain was removed for later determination of nimodi pine tissue concentration. The NP 15 mg group showed a significant dec line of 10% in MABP from base line to 24 h post implantation (p <0.001 ). All NP animals achieved at least 83% of their highest plasma concen tration at 1 h and 94% at 3 h. A high degree of correspondence (r(2)=0 .95, y=0.36+0.28 x, n=16) between the plasma and brain concentrations of nimodipine was present. Although a significant drop in MABP was obs erved the drop was no greater than 10% in 24 h. Plasma nimodipine leve ls for the 15 mg animals were within the cerebrovascular effective ran ge. This is the first report to show that 24 h release nimodipine pell ets subcutaneously implanted in rats are a reliable delivery system th at allows rapid rise and constant nimodipine plasma levels. Therefore, 24 h release pellets are a suitable alternative to other delivery sys tems like osmotic pumps.