Immunosuppressive Effect of Newly Developed Tacrolimus Emulsion in Liver Transplantation

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，这表明该药物在口服吸收方面有了改进。比较大鼠口服2 mg/kg他克莫司O/W乳剂(O/W组)后的全血血药浓度及1 mg/kg他克莫司O/W乳剂(T组)对大鼠骨髓、脾、肝、肺、小肠、肾、脑、全血分布的影响。制备后即刻乳滴平均直径为0.47微米。他克莫司O/W乳剂12h包封率为71.3%~5.0%，2d内无明显变化。0/W组全血浓度-时间曲线下面积显著高于T组(P<0.01)。而O/W组的恒定排泄率和总清除量显著低于T组(P<0.01)。相对生物利用度为115.9%。结果：1.与T组相比，O/W组大鼠骨髓、脾、肝、肺、小肠组织中他克莫司浓度显著升高，脑、肾组织中他克莫司浓度显著降低。我们研究了他克莫司O/W乳剂对大鼠心脏移植和肝移植的免疫抑制作用。研究发现，与商业配方相比，口服他克莫司O/W乳剂并不能更有效地延长大鼠心脏和肝脏移植物的存活时间。

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.