Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs

Pär Matsson; Jenny M Pedersen; Ulf Norinder; Christel A S Bergström; Per Artursson

doi:10.1007/s11095-009-9896-0

Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs

Pharm Res. 2009 Aug;26(8):1816-31. doi: 10.1007/s11095-009-9896-0. Epub 2009 May 7.

Authors

Pär Matsson¹, Jenny M Pedersen, Ulf Norinder, Christel A S Bergström, Per Artursson

Affiliation

¹ Pharmaceutical Screening and Informatics, Department of Pharmacy, Uppsala University, P.O. Box 580, 751 23, Uppsala, Sweden.

PMID: 19421845
DOI: 10.1007/s11095-009-9896-0

Abstract

Purpose: To study the inhibition patterns of the three major human ABC transporters P-gp (ABCB1), BCRP (ABCG2) and MRP2 (ABCC2), using a dataset of 122 structurally diverse drugs.

Methods: Inhibition was investigated in cellular and vesicular systems over-expressing single transporters. Computational models discriminating either single or general inhibitors from non-inhibitors were developed using multivariate statistics.

Results: Specific (n = 23) and overlapping (n = 19) inhibitors of the three ABC transporters were identified. GF120918 and Ko143 were verified to specifically inhibit P-gp/BCRP and BCRP in defined concentration intervals, whereas the MRP inhibitor MK571 was revealed to inhibit all three transporters within one log unit of concentration. Virtual docking experiments showed that MK571 binds to the ATP catalytic site, which could contribute to its multi-specific inhibition profile. A computational model predicting general ABC inhibition correctly classified 80% of both ABC transporter inhibitors and non-inhibitors in an external test set.

Conclusions: The inhibitor specificities of P-gp, BCRP and MRP2 were shown to be highly overlapping. General ABC inhibitors were more lipophilic and aromatic than specific inhibitors and non-inhibitors. The identified specific inhibitors can be used to delineate transport processes in complex experimental systems, whereas the multi-specific inhibitors are useful in primary ABC transporter screening in drug discovery settings.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / antagonists & inhibitors*
ATP-Binding Cassette Transporters / metabolism
Acridines / pharmacology
Adenosine / analogs & derivatives
Adenosine / pharmacology
Adenosine Triphosphate / metabolism
Cell Line
Computer Simulation
Diketopiperazines
Heterocyclic Compounds, 4 or More Rings
Humans
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
Multidrug Resistance-Associated Proteins / metabolism
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / metabolism
Propionates / pharmacology
Quinolines / pharmacology
Tetrahydroisoquinolines / pharmacology

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
ABCC2 protein, human
ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Acridines
Diketopiperazines
Heterocyclic Compounds, 4 or More Rings
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins
Neoplasm Proteins
Propionates
Quinolines
Tetrahydroisoquinolines
verlukast
Adenosine Triphosphate
Adenosine
Elacridar