Yamane Mizuki, Igarashi Fumihiko, Yamauchi Tsuyoshi, Nakagawa Toshito
Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
Xenobiotica. 2021 Jan;51(1):61-71. doi: 10.1080/00498254.2020.1812012. Epub 2020 Aug 30.
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 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 () 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.
UR-1102是一种用于治疗痛风的新型促尿酸排泄剂，已证实其在患者中具有药理作用。我们利用人体材料阐明了其代谢途径，估算了每种代谢酶的贡献，并评估了基因多态性的影响。在人肝细胞中检测到了UR-1102的葡萄糖醛酸化物、硫酸盐和氧化代谢物。人肝微粒体中葡萄糖醛酸化或氧化的内在清除率相当，但胞质溶胶中的硫酸化作用则低得多，这表明贡献顺序为葡萄糖醛酸化≥氧化＞硫酸化。重组UGT1A1和UGT1A3对UR-1102表现出较高的葡萄糖醛酸化作用。我们利用阿扎那韦对UGT同工型抑制敏感性的差异，估算出UGT1A1代谢分数（fm）为70%。使用重组细胞色素P450（CYPs）和CYP同工型特异性抑制剂的研究表明，氧化作用仅由CYP2C9介导。UGT1A1和CYP2C9抑制剂对肝细胞中UR-1102代谢的影响在野生型和变体之间没有显著差异。
