QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.106.012351v1 34/12/1976    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chang, C. Articles by Ekins, S. Search for Related Content PubMed PubMed Citation Articles by Chang, C. Articles by Ekins, S.

Rapid Identification of P-glycoprotein Substrates and Inhibitors

Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (C.C., P.M.B, J.E.P, P.W.S., S.E.); and ACT LLC, Jenkintown, Pennsylvania (S.E.)

Identifying molecules that interact with P-glycoprotein (P-gp) is important for drug discovery but is also generally reliant on time-consuming in vitro and in vivo studies. As an alternative approach, the current study applied pharmacophore models and database screening to rapidly retrieve molecules that bind as substrates or inhibitors for P-gp from commercial databases and then confirmed their affinity as inhibitors in vitro. Seven molecules (acitretin, cholecalciferol, misoprostol, nafcillin, repaglinide, salmeterol, and telmisartan) with no published details for P-gp affinity, one positive control inhibitor (miconazole), and two negative control molecules (phenelzine and zonisamide) were selected for testing. The MDCK-MDR1 in vitro cell model was used to confirm their inhibitory effect on [³H]digoxin transport, and the ATPase assay was used as an additional in vitro tool to indicate P-gp activation. All seven test drugs were confirmed to have P-gp affinity. Additionally, our experimental results provided plausible explanations for the published pharmacokinetic profiles of the tested drugs and their classification according to the biopharmaceutics and drug disposition classification system. In this study, we showed the successful application of pharmacophore models to accurately predict P-gp binding, which holds promise to anticipate drug-drug interactions from screening drug databases and a priori prediction of novel P-gp inhibitors or substrates.

This article has been cited by other articles:

				S. Ekins, V. Kholodovych, N. Ai, M. Sinz, J. Gal, L. Gera, W. J. Welsh, K. Bachmann, and S. Mani Computational Discovery of Novel Low Micromolar Human Pregnane X Receptor Antagonists Mol. Pharmacol., September 1, 2008; 74(3): 662 - 672. [Abstract] [Full Text] [PDF]

				K. Yasuda, A. Ranade, R. Venkataramanan, S. Strom, J. Chupka, S. Ekins, E. Schuetz, and K. Bachmann A Comprehensive in Vitro and in Silico Analysis of Antibiotics That Activate Pregnane X Receptor and Induce CYP3A4 in Liver and Intestine Drug Metab. Dispos., August 1, 2008; 36(8): 1689 - 1697. [Abstract] [Full Text] [PDF]

				D. S. Wishart, C. Knox, A. C. Guo, D. Cheng, S. Shrivastava, D. Tzur, B. Gautam, and M. Hassanali DrugBank: a knowledgebase for drugs, drug actions and drug targets Nucleic Acids Res., January 11, 2008; 36(suppl_1): D901 - D906. [Abstract] [Full Text] [PDF]

				P. Matsson, G. Englund, G. Ahlin, C. A. S. Bergstrom, U. Norinder, and P. Artursson A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2) J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 19 - 30. [Abstract] [Full Text] [PDF]