Abstract
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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Bandukwala, F., Huang, M., Zaltzman, J. S., Nash, M. M., and Prasad, G. V., Association of uric acid with inflammation, progressive renal allograft dysfunction and posttransplant cardiovascular risk. Am. J. Cardiol., 103, 867–871 (2009).
Baum, H., Hubsche, G., and Mahler, H. R., Studies on uricase. II. The enzyme-substrate complex. Biochim. Biophys. Acta, 22, 514–527 (1956).
Bertrand, Y., Mechinaud, F., Brethon, B., Mialou, V., Auvrignon, A., Nelken, B., Notz-Carrere, A., Plantaz, D., Patte, C., Urbieta, M., Baruchel, A., and Leverger, G., SFCE recommendations for the management of tumor lysis syndrome (TLS) with rasburicase: an observational survey. J. Pediatr. Hematol. Oncol., 30, 267–271 (2008).
Biggers, K. and Scheinfeld, N., Pegloticase, a polyethylene glycol conjugate of uricase for the potential intravenous treatment of gout. Curr. Opin. Investig. Drugs, 9, 422–429 (2008).
Bomalaski, J. S., Holtsberg, F. W., Ensor, C. M., and Clark, M. A., Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies. J. Rheumatol., 29, 1942–1949 (2002).
Bomalaski, J. S. and Clark, M. A., Serum uric acid-lowering therapies: where are we heading in management of hyperuricemia and the potential role of uricase. Curr. Rheumatol. Rep., 6, 240–247 (2004).
Bongaerts, G. P. A., Uitzetter, J., Brouns, R., and Vogels, G. D., Uricase of Bacillus fastidiosus: properties and regulation of synthesis. Biochem. Biophys. Acta, 527, 348–358 (1978).
Borinstein, S. C., Xu, M., and Hawkins, D. S., Methemoglobinemia and hemolytic anemia caused by rasburicase administration in a newly diagnosed child with Burkitt lymphoma/leukemia. Pediatr. Blood Cancer, 50, 189 (2008).
Bradford, M. M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 72, 248–254 (1976).
Browning, L. A. and Kruse, J. A., Hemolysis and methemoglobinemia secondary to rasburicase administration. Ann. Pharmacother., 39, 1932–1935 (2005).
Chohan, S. and Becker, M. A., Update on emerging uratelowering therapies. Curr. Opin. Rheumatol., 21, 143–149 (2009).
Conley, T. G. and Priest, D. G., Thermodynamics and stoichiometry of the binding of substrate analogues to uricase. Biochem. J., 187, 727–732 (1980).
Danhof, M., de Jongh, J., De Lange, E. C., Della Pasqua, O. E., Ploeger, B. A., and Voskuyl, R. A., Mechanism-based pharmacokinetic-pharmacodynamic modeling: biophase distribution, receptor theory, and dynamical systems analysis. Annu. Rev. Pharmacol. Toxicol., 47, 357–400 (2007).
Danhof, M., de Lange, E. C., Della Pasqua, O. E., Ploeger, B. A., and Voskuyl, R. A., Mechanism-based pharmacokineticpharmacodynamic (PK-PD) modeling in translational drug research. Trends Pharmacol. Sci., 29, 186–191 (2008).
Davidson, M. B., Thakkar, S., Hix, J. K., Bhandarkar, N. D., Wong, A., and Schreiber, M. J., Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am. J. Med., 116, 546–554 (2004).
Ducros, J., Saingra, S., Rampal, M., Coulange, C., Barbe, M. C., and Verzetti, G., Hemolytic anemia due to G6PD deficiency and urate oxidase in a kidney-transplant patient. Clin. Nephrol., 35, 89–90 (1991).
Feig, D. I., Kang, D. H., and Johnson, R. J., Uric acid and cardiovascular risk. N. Engl. J. Med., 359, 1811–1821 (2008).
Fridovich, I., The competitive inhibition of uricase by oxonate and by related derivatives of s-triazines. J. Biol. Chem., 240, 2491–2494 (1965).
Guo, R., Li, S. B., Zhao, L. N., Zhao, Y. S., Lu, W., Yuan, P., Deng, P., and Liao F., A new linearly-combined bi-exponential model for kinetic analysis of the isometric relaxation process of Bufo gastrocnemius under electric stimulation in vitro. J. Zhejiang Univ. Sci. B, 8, 867–874 (2007).
Hande, K. R., Perini, F., Putterman, G. J., and Elm, R., Hyperxanthinemia interferes with serum uric acid determinations by the uricase method. Clin. Chem., 25, 1492–1494 (1979).
Jeha, S., Kantarjian, H., Irwin, D., Shen, V., Shenoy, S., Blaney, S., Camitta, B., and Pui, C. H., Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: final results of a multicenter compassionate use trial. Leukemia, 19, 34–38 (2005).
Johnson, W. J., Stavric, B., and Chartrand, A., Uricase inhibition in the rat by s-triazines: an animal model for hyperuricemia and hyperuricosuria. Proc. Soc. Exp. Biol. Med., 131, 8–12 (1969).
Kang, D. H. and Nakagawa, T., Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease. Semin. Nephrol., 25, 43–49 (2005).
Kelly, S. J., Delnomdedieu, M., Oliverio, M. I., Williams, L. D., Saifer, M. G. P., Sherman, M. R., Coffman, T. M., Johnson, G. A., and Hershdield, M. S., Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase. J. Am. Soc. Nephrol., 12, 1001–1009 (2001).
Kizer, N., Martinez, E., and Powell, M., Report of two cases of rasburicase-induced methemoglobinemia. Leuk. Lym phoma, 47, 2648–2650 (2006).
Kynclova, E., Elsner, E., Kopf, A., Hawa, G., Schalkhammer, T., and Pittner, F., Novel method for coupling of poly (ethylene glycol) to carboxylic acid moieties of proteins. J. Mol. Recognit., 9, 644–651 (1996).
Liao, F., Liu, W. L., Zhou, Q. X., Zeng, Z. C., and Zuo, Y. P., Assay of serum arylesterase activity by fitting to the reaction curve with an integrated rate equation. Clin. Chim. Acta, 314, 67–76 (2001).
Liao, F., Zhu, X. Y., Wang, Y. M., and Zuo, Y. P., The comparison on the estimation of kinetic parameters by fitting enzyme reaction curve to the integrated rate equation of different predictor variables. J. Biochem. Biophys. Methods, 62, 13–24 (2005).
Liao, F., Zhao, Y. S., Zhao, L. N., Tao, J., Zhu, X. Y., and Liu, L., Evaluation of a kinetic uricase method for serum uric acid assay by predicting background absorbance of uricase reaction solution with an integrated method. J. Zhejiang Univ. Sci. B, 7, 497–502 (2006).
Liao, F., Yang, D. Y., Tang, J. Q., Yang, X. L., Liu, B. Z., Zhao, Y. S., Zhao, L. N., Liao, H., and Yu, M. A., The measurement of serum cholinesterase activities by an integration strategy with expanded linear ranges and negligible substrate-activation. Clin. Biochem., 42, 926–928 (2009).
Liu, B. Z., Zhao, Y. S., Zhao, L. N., Xie, Y. L., Zhu, S., Li, Z. R., Liu, Y., Lu, W., Yang, X. L., Xie, G. M., Zhong, H. S., Yu, M. A., Liao, H., and Liao, F., An integration strategy to estimate the initial rates of enzyme reactions with much expanded linear ranges using uricases as models. Anal. Chim. Acta, 631, 22–28 (2009a).
Liu, Z., Lu, D., Li, J., Chen, W., and Liu, Z., Strengthening intersubunit hydrogen bonds for enhanced stability of recombinant urate oxidase from Aspergillus flavus: molecular simulations and experimental validation. Phys. Chem. Chem. Phys., 11, 333–340 (2009b).
Mene, P. and Punzo, G., Uric acid: bystander or culprit in hypertension and progressive renal disease? J. Hypertens., 26, 2085–2092 (2008).
Nguyen, M. T., Awale, S., Tezuka, Y., Shi, L., Zaidi, S. F., Ueda, J. Y., Tran, Q. L., Murakami, Y., Matsumoto, K., and Kadota, S., Hypouricemic effects of acacetin and 4,5-o-dicaffeoylquinic acid methyl ester on serum uric acid levels in potassium oxonate-pretreated rats. Biol. Pharm. Bull., 28, 2231–2234 (2005).
Ramazzina, I., Folli, C., Secchi, A., Berni, R., and Percudani, R., Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes. Nat. Chem. Biol., 2, 144–148 (2006).
Sedor, F. A. and Sander, E. G., Inhibition of uricase by substituted pyrimidines. Biochem. Biophys. Res. Commun., 75, 406–413 (1977).
Sherman, M. R., Saifer, M. G. P., and Perez-Ruiz, F., PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv. Drug Deliv. Rev., 60, 59–68 (2008).
Stavric, B. and Nera, E. A., Use of the uricase-inhibited rat as an animal model in toxicology. Clin. Toxicol., 13, 47–74 (1978).
Sundy, J. S. and Hershfield, M. S., Uricase and other novel agents for the management of patients with treatmentfailure gout. Curr. Rheumatol. Rep., 9, 258–264 (2007).
Sundy, J. S., Ganson, N. J., Kelly, S. J., Scarlett, E. L., Rehrig, C. D., Huang, W., and Hershfield, M. S., Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum., 56, 1021–1028 (2007).
Tan, Q. Y., Wang, N., Yang, H., Zhang, L. K., Liu, S., Chen, L., Liu, J., Zhang, L., Hu, N. N., Zhao, C. J., and Zhang, J. Q., Characterization, stabilization and activity of uricase loaded in lipid vesicles. Int. J. Pharm., 384, 165–172 (2010).
Wu, X., Wakamiya, M., Vaishnav, S., Geske, R., Montgomery, C. M., Jones, P., Bradley, A., and Caskey, C. T., Hyperuricemia and urate nephropathy in urate oxidase-deficient mice. Proc. Natl. Acad. Sci. U.S.A., 91, 742–746 (1994).
Yue, C. S., Huang, W., Alton, M., Maroli, A. N., Waltrip, R. W., Wright, D., and Marco, M. D., Population pharmacokinetic and pharmacodynamic analysis of pegloticase in subjects with hyperuricemia and treatment-failure gout. J. Clin. Pharmacol., 48, 708–718 (2008).
Zhang, C., Yang, X. L., Feng, J., Yuan, Y. H., Li, X., Bu Y. Q., Xie, Y. L., Yuan, H. D., and Liao, F., Effects of modification of amino groups with poly(Ethylene Glycol) on a recombinant uricase from Bacillus fastidiosus. Biosci. Biotechnol. Biochem., 74, 1298–1301 (2010).
Zhao, Y. S., Zhao, L. N., Yang, G. Q., Tao, J., Bu, Y. Q., and Liao, F., Characterization of a uricase from Bacillus fastidious A.T.C.C. 26904 and its application to serum uric acid assay by a patented kinetic uricase method. Biotechnol. Appl. Biochem., 45, 75–80 (2006).
Zhao, Y. S., Yang, X. L., Li, X. Y., Bu, Y. Q., Deng, P., Zhang, C., Feng, J., Xie, Y. L., Zhu, S., Yuan, H. D., Yu, M. A., and Liao, F., Reversible inactivation of an intracellular uricase from Bacillus fastidiosus via dissociation of homotetramer into homodimers in solutions of low ionic strength. Biosci. Biotechnol. Biochem., 73, 2141–2144 (2009a).
Zhao, Y. S., Yang, X. Y., Lu, W., Liao, H., and Liao, F., Uricase based method for determination of uric acid in serum. Michrochim. Acta, 164, 1–6 (2009b).
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Feng, J., Li, X., Yang, X. et al. A new practical system for evaluating the pharmacological properties of uricase as a potential drug for hyperuricemia. Arch. Pharm. Res. 33, 1761–1769 (2010). https://doi.org/10.1007/s12272-010-1108-2
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DOI: https://doi.org/10.1007/s12272-010-1108-2