A new practical system for evaluating the pharmacological properties of uricase as a potential drug for hyperuricemia.
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.
Chongqing Medical University, China.
Juan
J
Feng
Xiang
X
Li
Xiaolan
X
Yang
Chun
C
Zhang
Yonghua
Y
Yuan
Jun
J
Pu
Yunsheng
Y
Zhao
Yanling
Y
Xie
Huidong
H
Yuan
Youquan
Y
Bu
Fei
F
Liao
D000818:Animals; D001407:Bacillus / Q000201:enzymology; D006073:Gout / Q000188:drug therapy*; D006207:Half-Life; D033461:Hyperuricemia / Q000188:drug therapy*; D008297:Male; D011092:Polyethylene Glycols / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014503:Urate Oxidase / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014527:Uric Acid / Q000097:blood*; D019820:Xanthine / Q000494:pharmacology
D019820:Xanthine; D014527:Uric Acid; D011092:Polyethylene Glycols; D014503:Urate Oxidase