Pharmacokinetics of a Micronized, Poorly Water-Soluble Drug, HO-221, in Experimental Animals.

Abstract

N-[[[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]amino]carbonyl]-2-nitrobenzamide (HO-221) is presently under development as an oral antivancer agent with a novel mode of action. However, HO-221 exhibits extremely poor bioavailability after oral administration because it is only slightly soluble in water (0.055μg/ml at 37°C). Our previous study revealed that the micronization of HO-221 to the submicron region improved this oral bioavailability. In this study, the oral pharmacokinetics of this micronized HO-221 was investigated in rats, dogs and monkeys. After oral administration, the agent was moderately absorbed with the T_max of 6.5-8.0, 17.3-20.0 and 12.0h, and eliminated with the terminal half-lives of 11.9-15.0, 66.8-78.3 and 42.3h in rats, dogs and monkeys, respectively. The bioavailability was incomplete (3.7-21.4%). In rats, the plasma concentration did not increase proportionally with increasing oral doses. In dogs, food enhanced the bioavailability 2.2-fold with a standard meal and 3.6-fold with a high fatty meal as compared with fasting conditions.