Disposition of KW-4679 (1) : Absorption, Distribution and Excretion of 14C-KW-4679 after Oral or Intravenous Administration to Rats
Disposition of KW-4679 (1) : Absorption, Distribution and Excretion of 14C-KW-4679 after Oral or Intravenous Administration to Rats
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KW-4679 的处置 (1)：大鼠口服或静脉给药后 14C-KW-4679 的吸收、分布和排泄
DOI：
10.2133/dmpk.10.651
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Satoshi Kobayashi
中科院分区：
文献类型：
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作者：
T. Ohishi;H. Nishiie;Hiroyuki Kobayashi;Satoshi Kobayashi
在雄性和雌性大鼠中研究了14 C-KW-4679以1 mg/kg剂量经口或静脉给药后的吸收、分布和排泄。还研究了雄性大鼠经口给予25 mg/kg剂量14 C-KW-4679后的吸收和排泄。1）经口给予1 mg/kg剂量14 C-KW-4679后，14 C-KW-4679被迅速吸收，吸收程度估计为91%或更高。推测药物主要在从十二指肠到空肠的区域吸收。2）禁食雄性大鼠经口给予1 mg/kg后，血浆放射性在0.5 h达到Cmax，然后呈双指数消失，终末半衰期为16.8 h。给药后96 h，42.6%和53.5%的给药放射性分别经尿液和粪便排泄。在胆汁中，给药后72 h排泄了46.0%的放射性。尿液、粪便和胆汁中的放射性排泄几乎在给药后24 h内完成。3）与禁食大鼠相比，非禁食大鼠经口给药后观察到Tmax延迟和Cmax降低。AUC 0-∞无显著差异。无论动物是否禁食，尿液和粪便中的放射性排泄均无差异。4）雌性大鼠经口给药后的AUC 0-∞比雄性大鼠大约18%。在雌性大鼠中证实了较低的粪便排泄和较高的尿液排泄的放射性趋势。5）禁食雄性大鼠静脉给予1 mg/kg后，放射性以三倍速率从血浆中消除，终末半衰期为34.2 h。给药后96 h，51.7%和43.0%的给药放射性经尿液和粪便排泄，6）禁食雄性大鼠经口给予1 mg/kg后，放射性迅速分布到几乎所有组织。除消化器官外，在肝脏、肾脏和膀胱中观察到高于血浆的放射性水平。在检查的所有器官中，在脑中观察到最低水平的放射性，其水平约为血浆的1/25。组织中的放射性几乎与血浆浓度平行消除。7）胆汁中排泄的放射性被重吸收（8.6%）。8）禁食雄性大鼠经口给予25 mg/kg剂量后血浆放射性的Tmax、剂量标准化Cmax和AUC 0-t分别几乎等于经口给予1 mg/kg剂量后的Tmax、剂量标准化Cmax和AUC 0-t。观察到25 mg/kg给药后的放射性尿排泄量高于1 mg/kg给药后。
The absorption, distribution and excretion of 14C-KW-4679 after oral or intravenous administration at a dose of 1 mg/kg were studied in male and female rats. Also the absorption and excretion of 14C-KW-4679 after oral administration at a dose of 25 mg/kg in male rats were studied.1) 14C-KW-4679 was rapidly absorbed and the extent of absorption was estimated to be 91% or higher after oral administration of 1 mg/kg. The drug was presumably absorbed mainly in the region from the duodenum to the jejunum.2) Plasma radioactivity reached Cmax at 0.5 hr after oral administration of 1 mg/kg to fasting male rats and then disappeared biexponentially with terminal half-life of 16.8 hr. By 96 hr after administration, 42.6% and 53.5% of the administered radioactivity were excreted in urine and feces, respectively. In bile, 46.0% of radioactivity was excreted by 72 hr after administration. The excretion of radioactivity in urine, feces and bile almost completed within 24 hr after administration.3) Delayed Tmax and reduced Cmax were observed after oral administration to non-fasting rats compared to fasting rats. There was no significant difference in AUC0-∞. No difference was observed in the excretion of radioactivity in urine and feces, whether animals were fasted or not.4) Larger AUC0-∞ by about 18% was obtained after oral administration to female rats as compared with male rats. A tendency of lower fecal excretion and higher urinary excretion of radioactivity was demonstrated in female rats.5) After intravenous administration of 1 mg/kg to fasting male rats, radioactivity was eliminated from plasma triexponentially with terminal half-life of 34.2 hr. By 96 hr after administration, 51.7% and 43.0%of the administered radioactivity were excreted in urine and feces, respectively.6) Radioactivity was rapidly distributed to almost all tissues after oral administration of 1 mg/kg to fasting male rats. Except digestive organs, higher than in plasma levels of radioactivity were observed in the liver, kidney and urinary bladder. The lowest level of radioactivity was observed in the brain, where the level was about 1/25 of that in plasma, among all the organs examined. Radioactivity in tissues was eliminated almost in parallel with plasma concentration.7) The radioactivity excreted in bile was reabsorbed (8.6%).8) Tmax, dose-normalized Cmax and AUC0-t of plasma radioactivity after oral administration at a dose of 25 mg/kg to fasting male rats was almost equal to that after oral administration at a dose of 1 mg/kg, respectively. Higher urinary excretion of radioactivity after 25 mg/kg dosing than that after 1 mg/kg dosing was observed.