Fujita Eriko, Teramura Yoshinori, Mitsugi Koichi, Ninomiya Shin-Ichi, Iwatsubo Takafumi, Kawamura Akio, Kamimura Hidetaka
Drug Metabolism Research Laboratories, Astellas Pharma Inc., Tokyo, Japan.
J Ocul Pharmacol Ther. 2008 Jun;24(3):333-43. doi: 10.1089/jop.2007.0086.
The aim of this study was to investigate the absorption, distribution, and excretion of radioactivity in male rabbits after a single or repeated instillation of (14)C-labeled tacrolimus (FK506) ophthalmic suspension or an intravenous (i.v.) administration of (14)C-FK506.
The 0.3% (14)C-FK506 suspension was administered in single and repeated (three times, 5-min intervals) instillation studies, and 1 mg/kg of (14)C-FK506 was administered in the i.v. dose study.
Results for single and repeated instillation studies were similar. In eyeball microautoradiograms, 15 min after dosing, the level of radioactivity in the cornea was the highest, followed by conjunctiva. After 1 h, little specific distribution was detected in the corneal epithelium, stroma, or Descemet's membrane. At 24 h, the level of radioactivity in the cornea decreased. Whole-body autoradiograms showed that the radioactivity was distributed to the digestive tract through the nasal meatus and esophagus and then was excreted into the feces. In the i.v. dose study, the distribution of radioactivity in whole-body autoradiographs was similar to that in quantitative tissue distribution measurements. The excretion of radioactivity in the urine and feces up to 168 h were 4.5 and 94.9%, respectively.
After the ocular instillation, FK506 is first absorbed in the cornea, conjunctiva, and nasolacrimal duct, and then the rest is distributed to digestive tract through the nasal meatus and esophagus, after which it is excreted mainly into the feces.
本研究旨在探讨单次或重复滴注（14）C 标记的他克莫司（FK506）眼用混悬液或静脉注射（14）C-FK506 后雄性兔体内放射性物质的吸收、分布和排泄情况。
在单次和重复（三次，间隔 5 分钟）滴注研究中给予 0.3%（14）C-FK506 混悬液，在静脉给药剂量研究中给予 1mg/kg 的（14）C-FK506。
单次和重复滴注研究结果相似。在眼球显微放射自显影片中，给药后 15 分钟，角膜中的放射性水平最高，其次是结膜。1 小时后，在角膜上皮、基质或后弹力层中未检测到明显的特异性分布。24 小时时，角膜中的放射性水平下降。全身放射自显影片显示，放射性物质通过鼻道和食管分布到消化道，然后排泄到粪便中。在静脉给药剂量研究中，全身放射自显影片中放射性物质的分布与定量组织分布测量结果相似。至 168 小时，尿液和粪便中放射性物质的排泄率分别为 4.5%和 94.9%。
眼部滴注后，FK506 首先在角膜、结膜和鼻泪管中吸收，其余部分则通过鼻道和食管分布到消化道，随后主要排泄到粪便中。
