Ramírez Jacqueline, Mirkov Snezana, House Larry K, Ratain Mark J
Department of Medicine, University of Chicago, Chicago, Illinois.
Department of Medicine, University of Chicago, Chicago, Illinois
Drug Metab Dispos. 2015 Jul;43(7):928-35. doi: 10.1124/dmd.115.063271. Epub 2015 Apr 13.
OTS167 is a potent maternal embryonic leucine zipper kinase inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (Km = 3.4 ± 0.2 µM), intestinal microsomes (HIM) (Km = 1.7 ± 0.1 µM), and UGTs. UGT1A1 (64 µl/min/mg) and UGT1A8 (72 µl/min/mg) exhibited the highest intrinsic clearances (CLint) for OTS167, followed by UGT1A3 (51 µl/min/mg) and UGT1A10 (47 µl/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r = 0.91, P < 0.0001), SN-38 glucuronidation (r = 0.79, P < 0.0001), and UGT1A1 mRNA (r = 0.72, P < 0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry. A significant association was found between rs6706232 and reduced OTS167-G formation (P = 0.03). No or weak UGT inhibition (range: 0-21%) was observed using clinically relevant OTS167 concentrations (0.4-2 µM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8, and UGT1A10 may contribute to first-pass OTS167 metabolism after oral administration.
OTS167是一种强效的母体胚胎亮氨酸拉链激酶抑制剂，正作为抗肿瘤药物进行临床试验。我们旨在确定参与OTS167代谢的尿苷二磷酸葡萄糖醛酸基转移酶（UGTs），研究UGT基因多态性与肝脏OTS167葡萄糖醛酸化之间的关系，并研究OTS167对UGTs的抑制潜力。在人肝微粒体（HLM）（Km = 3.4 ± 0.2 µM）、肠微粒体（HIM）（Km = 1.7 ± 0.1 µM）和UGTs中均观察到单一的OTS167-葡萄糖醛酸化物（OTS167-G）的形成。UGT1A1（64 µl/min/mg）和UGT1A8（72 µl/min/mg）对OTS167表现出最高的内在清除率（CLint），其次是UGT1A3（51 µl/min/mg）和UGT1A10（47 µl/min/mg）；UGT1A9的贡献较小。HLM中OTS167的葡萄糖醛酸化与甲状腺素葡萄糖醛酸化（r = 0.91，P < 0.0001）、SN-38葡萄糖醛酸化（r = 0.79，P < 0.0001）和UGT1A1 mRNA（r = 0.72，P < 0.0001）高度相关。尼罗替尼（UGT1A1抑制剂）和大黄素（UGT1A8和UGT1A10抑制剂）对HLM（68%）和HIM（47%）中OTS167-G的形成表现出最高的抑制作用。根据质谱分析，我们推测OTS167-G是一种N-葡萄糖醛酸化物。发现rs6706232与OTS167-G形成减少之间存在显著关联（P = 0.03）。使用临床相关的OTS167浓度（0.4 - 2 µM）未观察到或仅观察到较弱的UGT抑制作用（范围：0 - 21%）。我们得出结论，UGT1A1和UGT1A3是负责肝脏中OTS167-G形成的主要UGTs。肠道中的UGT1A1、UGT1A8和UGT1A10可能在口服给药后对OTS167的首过代谢有贡献。
