Pharmacokinetics of a micronized, poorly water-soluble drug, HO-221, in experimental animals.
N-[[[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]amino]carbonyl] - 2-nitrobenzamide (HO-221) is presently under development as an oral anticancer 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 (0.055 micrograms/ml at 37 degrees 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 Tmax of 6.5-8.0, 17.3-20.0 and 12.0 h, and eliminated with the terminal half-lives of 11.9-15.0, 66.8-78.3 and 42.3 h 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.
Kondo
N
N
Research Division, Green Cross Corp, Osaka, Japan.
Iwao
T
T
Kikuchi
M
M
Shu
H
H
Yamanouchi
K
K
Yokoyama
K
K
Ohyama
K
K
Ogyu
S
S
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D004041:Dietary Fats / Q000494:pharmacology; D004285:Dogs; D005502:Food; D006207:Half-Life; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D009578:Nitrobenzenes / Q000097:blood / Q000493:pharmacokinetics*; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D000970:Antineoplastic Agents; D001549:Benzamides; D004041:Dietary Fats; D009578:Nitrobenzenes; D011208:Powders; C066688:N-(4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl)-N'-(2-nitrobenzoyl)urea