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KMID : 0043320100330111761
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Archives of Pharmacal Research
2010 Volume.33 No. 11 p.1761 ~ p.1769
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A new practical system for evaluating the pharmacological properties of uricase as a potential drug for hyperuricemia
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Feng Juan
Li Xiang
Yang Xiaolan
Zhang Chun
Yuan Yonghua
Pu Jun
Zhao Yunsheng
Xie Yanling
Yuan Huidong
Bu Youquan
Liao Fei
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Abstract
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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 uricase, 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 uricase 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.
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KEYWORD
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Hyperuricemia, Uricase, Pharmacokinetics, Pharmacodynamics, Half-life time, Mathematic modeling
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