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Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2
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.
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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis