Metabolism of KO143, an ABCG2 inhibitor

Ke Liu; Junjie Zhu; Yixian Huang; Chaoyue Li; Jie Lu; Madhav Sachar; Song Li; Xiaochao Ma

doi:10.1016/j.dmpk.2017.02.003

Metabolism of KO143, an ABCG2 inhibitor

Drug Metab Pharmacokinet. 2017 Aug;32(4):193-200. doi: 10.1016/j.dmpk.2017.02.003. Epub 2017 Mar 6.

Authors

Ke Liu¹, Junjie Zhu¹, Yixian Huang¹, Chaoyue Li², Jie Lu¹, Madhav Sachar¹, Song Li¹, Xiaochao Ma³

Affiliations

¹ Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
² Department of Neurosurgery, Henan People's Hospital, Zhengzhou, China.
³ Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: mxiaocha@pitt.edu.

PMID: 28619281
DOI: 10.1016/j.dmpk.2017.02.003

Abstract

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.

Keywords: ABCG2; Carboxylesterase; Drug design; Drug metabolism; KO143.

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
Animals
Diketopiperazines / chemistry
Diketopiperazines / metabolism*
Diketopiperazines / pharmacology
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / metabolism*
Heterocyclic Compounds, 4 or More Rings / pharmacology
Humans
Male
Mice
Mice, Inbred Strains
Molecular Conformation
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / metabolism
Tissue Distribution

Substances

3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester
ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 2
Diketopiperazines
Heterocyclic Compounds, 4 or More Rings
Neoplasm Proteins