Xie Qiushi, Chen Yang, Liu Fei, Zhong Zeyu, Zhao Kaijing, Ling Zhaoli, Wang Fan, Tang Xiange, Wang Zhongjian, Liu Li, Liu Xiaodong
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Drug Metab Pharmacokinet. 2016 Aug;31(4):314-22. doi: 10.1016/j.dmpk.2016.05.002. Epub 2016 May 15.
Deoxypodophyllotoxin (DPT) is a natural lignan product which has drawn much attention due to its pharmacological properties including antitumor effect. The purpose of this study was to investigate interspecies differences in metabolism of DPT in hepatic microsomes from human (HLM), cynomolgus monkey (CyLM), rat (RLM), mouse (MLM) and dog (DLM). Incubation of DPT with hepatic microsomes from five species in the presence of NADPH resulted in formation of seven metabolites, five of which were compared with the synthetic standards. M2 was the most abundant metabolite in microsomes from all species. Rank order of intrinsic clearance for M2 formation was RLM > CyLM > MLM > HLM > DLM. In HLM, sulfaphenazole showed the strongest inhibition effect on M2 formation, but neither ticlopidine nor ketoconazole inhibited M2 formation in HLM. Results from cDNA-expressed human CYP450s experiments showed that clearance of M2 formation was much higher in CYP2C9 and CYP2C19 than that in CYP3A4. Contributions of the three CYP450 isoforms to M2 formation in HLM were estimated using relative activity factor (RAF) method or correction by amount of CYP450 isoforms in HLM. M2 formation in HLM was mainly attributed to CYP2C9, followed by CYP2C19. Involvement of CYP3A4 was minor.
脱氧鬼臼毒素（DPT）是一种天然木脂素类产物，因其包括抗肿瘤作用在内的药理特性而备受关注。本研究的目的是调查人（HLM）、食蟹猴（CyLM）、大鼠（RLM）、小鼠（MLM）和犬（DLM）肝脏微粒体中DPT代谢的种间差异。在NADPH存在的情况下，将DPT与五种物种的肝脏微粒体一起孵育，产生了七种代谢产物，其中五种与合成标准品进行了比较。M2是所有物种微粒体中含量最丰富的代谢产物。形成M2的内在清除率的排序为RLM＞CyLM＞MLM＞HLM＞DLM。在HLM中，磺胺苯吡唑对M2的形成表现出最强的抑制作用，但噻氯匹定和酮康唑均未抑制HLM中M2的形成。来自cDNA表达的人CYP450实验的结果表明，CYP2C9和CYP2C19中M2形成的清除率远高于CYP3A4。使用相对活性因子（RAF）方法或通过HLM中CYP450同工型的量进行校正，估计了三种CYP450同工型对HLM中M2形成的贡献。HLM中M2的形成主要归因于CYP2C9，其次是CYP2C19。CYP3A4的参与程度较小。
