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Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2011 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 13, 4548-4558 p.Article in journal (Refereed) Published
Abstract [en]

Drug-drug interactions (DDIs) are major causes of serious adverse drug reactions. Most DDIs have a pharmacokinetic basis in which one drug reduces the elimination of a second drug, leading to potentially toxic drug levels. As a major organ of drug elimination, the kidney represents an important site for DDIs. Here, we screened a prescription drug library against the renal organic cation transporter OCT2/SLC22A2, which mediates the first step in the renal secretion of many cationic drugs. Of the 910 compounds screened, 244 inhibited OCT2. Computational analyses revealed key properties of inhibitors versus noninhibitors, which included overall molecular charge. Four of six potential clinical inhibitors were transporter-selective in follow-up screens against additional transporters: OCT1/SLC22A1, MATE1/SLC47A1, and MATE2-K/SLC47A2. Two compounds showed different kinetics of interaction with the common polymorphism OCT2-A270S, suggesting a role of genetics in modulating renal DDIs.

Place, publisher, year, edition, pages
2011. Vol. 54, no 13, 4548-4558 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-175842DOI: 10.1021/jm2001629PubMedID: 21599003OAI: oai:DiVA.org:uu-175842DiVA: diva2:533220
Note

De två första författarna delar förstaförfattarskapet

Available from: 2012-06-13 Created: 2012-06-13 Last updated: 2017-12-07Bibliographically approved

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