Kondo N, Iwao T, Kikuchi M, Shu H, Yamanouchi K, Yokoyama K, Ohyama K, Ogyu S
Research Division, Green Cross Corp, Osaka, Japan.
Biol Pharm Bull. 1993 Aug;16(8):796-800. doi: 10.1248/bpb.16.796.
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.
N-[[[4-(5-溴-2-嘧啶氧基)-3-氯苯基]氨基]羰基]-2-硝基苯甲酰胺（HO-221）目前正作为一种具有新型作用模式的口服抗癌药物进行研发。然而，HO-221口服给药后生物利用度极低，因为它在水中的溶解度很小（37℃时为0.055微克/毫升）。我们之前的研究表明，将HO-221微粉化至亚微米区域可提高其口服生物利用度。在本研究中，对这种微粉化的HO-221在大鼠、狗和猴子体内的口服药代动力学进行了研究。口服给药后，该药物吸收适中，大鼠、狗和猴子的达峰时间分别为6.5 - 8.0、17.3 - 20.0和12.0小时，消除半衰期分别为11.9 - 15.0、66.8 - 78.3和42.3小时。生物利用度不完全（3.7 - 21.4%）。在大鼠中，血浆浓度并未随口服剂量增加而成比例增加。在狗中，与禁食条件相比，标准餐使生物利用度提高了2.2倍，高脂餐使其提高了3.6倍。
