A New Practical System for Evaluating the Pharmacological Properties of Uricase as a Potential Drug for Hyperuricemia
A New Practical System for Evaluating the Pharmacological Properties of Uricase as a Potential Drug for Hyperuricemia
复制标题
评估尿酸酶作为高尿酸血症潜在药物的药理特性的新实用系统
DOI：
10.1007/s12272-010-1108-2
复制
发表时间：
2010-11-01
影响因子：
6.7
通讯作者：
Liao, Fei
中科院分区：
文献类型：
--
作者：
Feng, Juan;Li, Xiang;Liao, Fei
使用尿酸酶缺陷的哺乳动物筛选工程尿酸酶制剂作为高尿酸血症的潜在药物涉及高昂的成本并存在技术瓶颈。在此，研究了一种新的实用系统，以基于细菌尿酸酶体外消除血浆中尿酸的能力、其在健康大鼠中的体内药代动力学和体内模拟药效学来评估细菌尿酸酶的药理学意义。用聚甲基醚改性前后（乙二醇）5000，有效地消除尿酸在体外兔血浆中，但其作用是易受黄嘌呤抑制静脉注射后的修饰尿酸酶未经纯化，双指数模型很好地拟合健康大鼠血浆中体内尿酸酶活性。来自样品中剩余的未修饰的尿酸酶的干扰，并且比未修饰的尿酸酶的干扰长近100倍。使用考虑尿酸酶药代动力学和黄嘌呤抑制的体内尿酸消除模型，模拟的药效学支持不安的半衰期及其对黄嘌呤的敏感性对于尿酸酶的药理学意义是至关重要的。因此，该实用系统对于初步筛选作为高尿酸血症潜在药物的工程尿酸酶制剂是理想的
The use of uricase deficient mammals to screen formulations of engineered uricases as potential drugs for hyperuricemia involves heavy costs and presents a technical bottleneck Herein, a new practical system was investigated to evaluate the pharmacological significance of a bacterial uricase based on its ability to eliminate uric acid in plasma in vitro, its pharmacokinetics in vivo in healthy rats, and the modeled pharmacodynamics in vivo This unease, before and after modification with the monomethyl ether of poly(ethylene glycol) 5000, effectively eliminated uric acid in vitro in rabbit plasma, but its action was susceptible to xanthine inhibition After intravenous injection of the modified uricase without purification, a bi exponential model fit well to uricase activities in vivo in the plasma of healthy rats the half life of the modified uricase was estimated without interference from the unmodified uricase leftover in the sample and was nearly 100 fold longer than that of the unmodified uricase Using a model of the elimination of uric acid in vivo taking into account of uricase pharmacokinetics and xanthine inhibition, modeled pharmacodynamics supported that the half life of unease and its susceptibility to xanthine are crucial for the pharmacological significance of uricase Hence, this practical system is desirable for doing preliminary screening of formulations of engineered uricases as potential drugs for hyperuricemia