Immunosuppressive Effect of Newly Developed Tacrolimus Emulsion in Liver Transplantation

新研制的他克莫司乳剂在肝移植中的免疫抑制作用

• 批准号: 08671352
• 负责人: UNO Takeji
• 金额: $ 1.47万
• 依托单位: Hamamatsu University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671352/
• 关键词: Tacrolimus; Water-in-Oil-in-Water-Type Multiple Emulsion; Oil-in-Water-Type Emulsion; Immunosuppressive effect; Wエマルション; ラット心移植; ラット肝移植; 急性移植片対宿主病治療; 経口用タクロリムス; o; wエマルション; 心移植; 肝移植; 薬物動態

1. We developed an oleic acid oil-in-water(o/w)-type emulsion of a new tacrolimus formulation that represented an improvement in the delivery of the drug for oral absorption. The whole blood concentration profiles after oral administration at dose of 2mg/kg and bone marrow, spleen, liver, lung, small intestine, kidney, brain, and whole blood distribution after oral administration at dose of 1mg/kg of o/w emulsion formulation of tacrolimus (O/W group) were compared with those of commercially available formulation (T group) in the rat. The mean diameters of the olw emulsion droplets were 0.47 mu m immediately after it's preparation. The tacrolimus entrapping efficiency of o/w emulsion was 71.3 5.0% in 12 hrs and did not change for 2 days. The value of area under the whole blood concentration- time curve in the 0/W group was significantly higher (p<0.01) than that in the T group. In contrast, the values of constant elimination rate and total clearance in the O/W group were significantly lower (p<0.01) than those in the T group. The value of comparative bioavailability was 115.9%. The tissue concentration values of tacrolimus in the O/W group demonstrated significantly increased levels in the bone marrow, spleen, liver, lung, and small intestine, and significantly decreased levels in the brain and kidney, relative to the T group.2. We investigated the immunosuppressive effects of tacrolimus o/w emulsion in rat cardiac allografts and liver allografts. It has found that the oral administration of tacrolimus o/w emulsion is not more effective in prolonging survival of cardiac and liver allografts in rats, relative to the commercially available formulation.

1.我们开发了一种新的他克莫司制剂的油酸水包油（o/w）型乳剂，该乳剂代表了口服吸收药物递送的改善。比较了大鼠经口给予2 mg/kg他克莫司o/w乳剂（O/W组）和市售制剂（T组）后的全血浓度曲线和经口给予1 mg/kg他克莫司o/w乳剂（O/W组）后的骨髓、脾、肝、肺、小肠、肾、脑和全血分布。olw乳液液滴的平均直径为0.47 μ m。O/W型乳剂的包封率在12小时内为71.3 ± 5.0%，2天内无变化。0/W组全血浓度-时间曲线下面积值显著高于T组（p<0.01）。O/W组的恒定消除率和总清除率明显低于T组（P<0.01）。相对生物利用度为115.9%。与T组相比，O/W组的他克莫司在骨髓、脾、肝、肺和小肠中的组织浓度值显著升高，而在脑和肾中的组织浓度值显著降低.我们研究了他克莫司O/W乳剂在大鼠同种异体心脏移植和同种异体肝脏移植中的免疫抑制作用。已经发现，相对于市售制剂，他克莫司o/w乳剂的口服给药在延长大鼠心脏和肝脏同种异体移植物的存活方面并不更有效。

项目成果

Uno, T., et al.: "Pharmacokinetic Advantages of Newly Developed Tacrolimus Oil-inーWater-Type Emulsion via the Enteral Reute" Lipids. 34. (1999)

Uno, T., et al.：“新开发的他克莫司水包油型乳剂通过肠内途径的药代动力学优势”34。(1999)

Takeji Uno, et al.: "The Pharmacokinetics of Water-in-Oil-in-Water-Type Multiple Emulsion of a New Tacrolimus Formulation" Lipids. 32・5. 543-548 (1997)

Takeji Uno等人：“新他克莫司制剂的水包油包水型多重乳剂的药代动力学”脂质32・5（1997）。

Takeji Uno, Takaji Yamaguchi, Xiao Kang Li, Yoshinari Suzuki, Hisakuni Hashimoto, Yukio Harada, Taizo Kimura, and Teruhisa Kazui: "The Pharmacokinetics of Water-in-Oil-in-Water-Type Multiple Emulsion of a New Tacrolimus Formulation" Lipids. Vol.32, no.5.

Takeji Uno、Takaji Yamaguchi、Xiao Kang Li、Yoshinari Suzuki、Hisakuni Hashimoto、Yukio Harada、Taizo Kimura 和 Teruhisa Kazui：“他克莫司新配方的水包油包水型多重乳剂的药代动力学”

Takeji Uno, Teruhisa Kazui, Yoshinari Suzuki, Hisakuni Hashimoto, Koichi Suzuki, and Bashar A.H.Muhammad: "Phamacokinetic Advantages of Newly Developed Tacrolimus Oil-in-Water-Type Emulsion via the Enteral Route" Lipids. Vol.34. (1999)

Takeji Uno、Teruhisa Kazui、Yoshinari Suzuki、Hisakuni Hashimoto、Koichi Suzuki 和 Bashar A.H.Muhammad：“新开发的他克莫司水包油型乳剂通过肠内途径的药代动力学优势”脂质。

Takeji Uno: "The Pharmacokinetics of Water-in Oil-in-Water-Type Multiple Emulsion of a New Tacrolimus Formulation" Lipids. 32・5. 543-548 (1997)

Takeji Uno：“他克莫司新制剂的水包油包水型多重乳剂的药代动力学”32・5（1997）。