Preparation and evaluation of suppositories for RK-28 (a new radiosensitizer) using rabbits

The pharmacokinetics of RK-28 [1-(4-hydroxy-2-butenoxy)methyl-2-nitroimidazole], a new hypoxic cell radiosensitizer, was studied following intravenous, oral, and rectal administration to rabbits. After an oral administration of RK-28 solution, the plasma concentration of RK-28 was considerably lower than that after intravenous administration through all time periods, and the absolute bioavailability was a mere 4.2%. It was presumed that a specific acid-catalyzed decomposition of RK-28 progressed in the stomach, and also, the absorbed RK-28 suffered first-pass effects in the liver. In contrast, the absolute bioavailability following the rectal administration of a solidified RK-28 suppository preparation was significantly increased in comparison with that obtained by other administration routes. Also, RK-28 emulsion suppositories were prepared by emulsifying various amounts of the drug with 1-hexadecanol and hydrogenated castor oil (HCO 60) at 80degC, and these were administered into the rabbit rectum. The resulting absolute bioavailability was 91% for the RK-28 emulsion suppository and 86.9% for an RK-28 emulsion suppository containing small amounts of Eudispert hv. These values were better than those in rats. The rectal administration of the RK-28 emulsion suppository containing small amounts of Eudispert hv showed a preferable plasma concentration-time pattern that reflects on radiation therapy. (author)