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Abstract
UR-1102, a novel uricosuric agent for treating gout, has been confirmed to exhibit a pharmacological effect in patients. We clarified its metabolic pathway, estimated the contribution of each metabolic enzyme, and assessed the impact of genetic polymorphisms using human in vitro materials.
Glucuronide, sulfate and oxidative metabolites of UR-1102 were detected in human hepatocytes.
The intrinsic clearance by glucuronidation or oxidation in human liver microsomes was comparable, but sulfation in the cytosol was much lower, indicating that the rank order of contribution was glucuronidation ≥ oxidation > sulfation.
Recombinant UGT1A1 and UGT1A3 showed high glucuronidation of UR-1102. We took advantage of a difference in the inhibitory sensitivity of atazanavir to the UGT isoforms and estimated the fraction metabolised (fm) with UGT1A1 to be 70%.
Studies using recombinant CYPs and CYP isoform-specific inhibitors showed that oxidation was mediated exclusively by CYP2C9.
The effect of UGT1A1 and CYP2C9 inhibitors on UR-1102 metabolism in hepatocytes did not differ markedly between the wild type and variants.
Acknowledgements
The authors thank Chugai team members and colleagues, especially Kosuke Kawashima and Naoshi Horiba, for their valuable role in the development of UR-1102 and for assisting with preparation of the manuscript. We thank Yuka Shinohara, Naoki Takahashi and Ayako Nakamura for their help in our studies, and Jacob Davis and Sally Matsuura for their editing advice. We also thank our colleagues at JW Pharmaceutical Corp. who assisted with preparation of the manuscript.
Disclosure statement
The authors of this work are employees of Chugai Pharmaceutical and have not received financial support from any other institution.