PHARMACOKINETICS, TOXICITY, SIDE-EFFECTS, RECEPTOR AFFINITIES AND IN-VITRO RADIOSENSITIZING EFFECTS OF THE NOVEL METOCLOPRAMIDE FORMULATIONS, SENSAMIDE AND NEU-SENSAMIDE

Metoclopramide is a drug which has experienced worldwide use in the cl inic for over 30 years as an antiemetic. Recently, it has also been sh own to possess radio- and chemosensitizing properties in both animal t umour models and humans at the higher dose of 2 mg/kg. Two new metoclo pramide formulations are being clinically developed and they differ ma inly in whether the pH of their formulations are acidic (pH 2.5-3.5) o r neutral (pH 6.5-7.0). Here we report that intramuscular administrati on of neutral metoclopramide is about 100% bioavailable, safer and wit h reduced side effects compared to acidic metoclopramide delivered by intramuscular injection to rats within the dose range of 3.5 to 14 mg/ kg. The intramuscular administration of metoclopramide was also about 100% bioavailable compared to the intravenous route of administration. Furthermore, neutral metoclopramide had significantly decreased affin ity for dopamine D-2 receptors and increased affinity for 5-hydroxytry ptamine(3) receptors, but the radiosensitizing potency was the same, w hen compared to equimolar concentrations of acidic metoclopramide. Tak en together these data support the continued development of neutral me toclopramide for high dose intramuscular administration of metoclopram ide for future clinical use as both an antiemetic and radiosensitizer.