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J Pharmacol Exp Ther. 2015 Sep;354(3):384-93. doi: 10.1124/jpet.115.225482. Epub 2015 Jul 6.

The Inhibitor Ko143 Is Not Specific for ABCG2.

Author information

1
Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.) lora.deuitch@nih.gov.
2
Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).

Abstract

Imaging ATP-binding cassette (ABC) transporter activity in vivo with positron emission tomography requires both a substrate and a transporter inhibitor. However, for ABCG2, there is no inhibitor proven to be specific to that transporter alone at the blood-brain barrier. Ko143 [[(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4- b]indole-3-propanoic acid 1,1-dimethylethyl ester], a nontoxic analog of fungal toxin fumitremorgin C, is a potent inhibitor of ABCG2, although its specificity in mouse and human systems is unclear. This study examined the selectivity of Ko143 using human embryonic kidney cell lines transfected with ABCG2, ABCB1, or ABCC1 in several in vitro assays. The stability of Ko143 in rat plasma was measured using high performance liquid chromatography. Our results show that, in addition to being a potent inhibitor of ABCG2, at higher concentrations (≥1 μM) Ko143 also has an effect on the transport activity of both ABCB1 and ABCC1. Furthermore, Ko143 was found to be unstable in rat plasma. These findings indicate that Ko143 lacks specificity for ABCG2 and this should be taken into consideration when using Ko143 for both in vitro and in vivo experiments.

PMID:
26148857
PMCID:
PMC4538874
DOI:
10.1124/jpet.115.225482
[Indexed for MEDLINE]
Free PMC Article

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