Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology and Safety Science, R&D, AstraZeneca Gothenburg, Sweden.
Functional and Mechanistic Safety Hepatic Safety, Clinical Pharmacology and Safety Science, R&D, AstraZeneca Gothenburg, Sweden.
J Pharm Sci. 2020 Jul;109(7):2309-2320. doi: 10.1016/j.xphs.2020.03.013. Epub 2020 Apr 12.
The pharma industry designs increasingly less cytochrome P450 dependent and more metabolically stable drugs, and consequently UGT-metabolism becomes more frequently involved. This study compares 2 glucuronidation RAF-scaling approaches, product formation and substrate depletion, regarding their potential for prediction of in vivo DDI and the relative contribution of UGT-mediated phase II reactions in an industrial setting. RAFs were developed for UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7 and 2B15 recombinant UGT isoforms and a large 150-donor pooled human liver microsome batch. The RAF-values ranged from small values of 0.06 (UGT1A3), over 0.24 and 0.48 (UGT1A9 and UGT1A4), to values around 1 (1.11 for UGT2B7, 1.14 for UGT1A1), and high RAFs of 4.8 (UGT1A6) and 6.57 (UGT2B15). Both approaches identified the same primarily involved isoforms (≥75% relative contribution) of 5 clinical reference compounds (raloxifene, haloperidol, laropiprant, telmisartan and naloxone), in concordance with reported in vitro (R2 = 0.65) and clinical results for UGT1A1, 1A3, 1A4, 1A9, 2B7 and 2B15. This study is distinctive in that it is reporting the glucuronide formation in addition to substrate depletion. The product formation approach proved more sensitive and enables UGT phenotyping of slowly metabolized drugs, additionally it allows identification of structurally different glucuronides.
制药行业设计的药物越来越少依赖细胞色素 P450，而更多地依赖代谢稳定性，因此 UGT 代谢越来越频繁地参与其中。本研究比较了两种葡萄糖醛酸化 RAF 缩放方法，即产物形成和底物耗竭，探讨了它们在工业环境中预测体内 DDI 的潜力以及 UGT 介导的 II 相反应的相对贡献。RAFs 是针对 UGT1A1、1A3、1A4、1A6、1A9、2B7 和 2B15 重组 UGT 同工酶以及大量 150 个供体混合人肝微粒体批次开发的。RAF 值的范围从较小的值 0.06（UGT1A3），到 0.24 和 0.48（UGT1A9 和 UGT1A4），再到约 1（UGT2B7 为 1.11，UGT1A1 为 1.14），以及高 RAF 值 4.8（UGT1A6）和 6.57（UGT2B15）。两种方法都确定了相同的主要参与同工酶（≥75%的相对贡献），用于 5 种临床参考化合物（raloxifene、haloperidol、laropiprant、telmisartan 和 naloxone），与报道的体外（R2=0.65）和临床结果（UGT1A1、1A3、1A4、1A9、2B7 和 2B15）一致。本研究的独特之处在于它除了报告底物耗竭外，还报告了葡萄糖醛酸化物的形成。产物形成方法更灵敏，能够对代谢缓慢的药物进行 UGT 表型分析，此外，它还能够识别结构不同的葡萄糖醛酸化物。
