Liu Ke, Zhu Junjie, Huang Yixian, Li Chaoyue, Lu Jie, Sachar Madhav, Li Song, Ma Xiaochao
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Neurosurgery, Henan People's Hospital, Zhengzhou, China.
Drug Metab Pharmacokinet. 2017 Aug;32(4):193-200. doi: 10.1016/j.dmpk.2017.02.003. Epub 2017 Mar 6.
The ATP-binding cassette sub-family G member 2 (ABCG2) plays an important role in modulating drug disposition and endobiotic homeostasis. KO143 is a potent and relatively selective ABCG2 inhibitor. We found that the metabolic stability of KO143 was very poor in human liver microsomes (HLM). Our further studies illustrated that the tert-butyl ester group in KO143 can be rapidly hydrolyzed and removed by carboxylesterase 1. This metabolic pathway was confirmed as a major pathway of KO143 metabolism in both HLM and mice. K1 is an analog of KO143 without the ester group. We found that the metabolic stability of K1 was significantly improved in HLM when compared to KO143. These data suggest that the ester group in KO143 is the major cause of the poor metabolic stability of KO143. The data from this study can be used to guide the development of KO143 analogs with better metabolic properties.
ATP结合盒转运体G亚家族成员2（ABCG2）在调节药物处置和内源性物质稳态方面发挥着重要作用。KO143是一种强效且相对选择性的ABCG2抑制剂。我们发现KO143在人肝微粒体（HLM）中的代谢稳定性非常差。我们进一步的研究表明，KO143中的叔丁酯基团可被羧酸酯酶1快速水解并去除。该代谢途径被确认为KO143在HLM和小鼠体内代谢的主要途径。K1是KO143的一种无酯基团类似物。我们发现，与KO143相比，K1在HLM中的代谢稳定性显著提高。这些数据表明，KO143中的酯基团是其代谢稳定性差的主要原因。本研究的数据可用于指导开发具有更好代谢特性的KO143类似物。
