Abstract

1. 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.

2. Glucuronide, sulfate and oxidative metabolites of UR-1102 were detected in human hepatocytes.

3. 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.

4. 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%.

5. Studies using recombinant CYPs and CYP isoform-specific inhibitors showed that oxidation was mediated exclusively by CYP2C9.

6. The effect of UGT1A1 and CYP2C9 inhibitors on UR-1102 metabolism in hepatocytes did not differ markedly between the wild type and variants.

摘要

1. UR-1102是一种新型的治疗痛风的尿酸尿酸药物，已被证实对患者具有药理作用。我们阐明了其代谢途径，估计了每种代谢酶的作用，并使用人类体外材料评估了遗传多态性的影响。

2. 在人肝细胞中检测到了UR-1102的葡萄糖醛酸，硫酸盐和氧化代谢产物。

3. 在人肝微粒体中通过葡萄糖醛酸化或氧化的固有清除率是可比较的，但是在细胞溶胶中的硫酸化作用要低得多，表明贡献的等级顺序是葡萄糖醛酸化≥氧化>硫酸化作用。

4. 重组UGT1A1和UGT1A3显示UR-1102的葡萄糖醛酸高糖化。我们利用了阿扎那韦对UGT同工型的抑制敏感性差异，并估计UGT1A1的代谢率（fm）为70％。

5. 使用重组CYP和CYP亚型特异性抑制剂的研究表明，氧化仅由CYP2C9介导。

6. UGT1A1和CYP2C9抑制剂对肝细胞中UR-1102代谢的影响在野生型和变异型之间没有显着差异。