Authors: Lei Diao Sean Ekins James E Polli
Publish Date: 2009/05/13
Volume: 26, Issue: 8, Pages: 1890-1900
Abstract
Twentyseven drugs were screened initially for their potential to inhibit uptake of lcarnitine into a stably transfected hOCTN2MDCK cell monolayer A HipHop common features pharmacophore was developed and used to search a drug database Fiftythree drugs including some not predicted to be inhibitors were selected and screened in vitroA common features pharmacophore was derived from initial screening data and consisted of three hydrophobic features and a positive ionizable feature Among the 33 tested drugs that were predicted to map to the pharmacophore 27 inhibited hOCTN2 in vitro 40 or less lcarnitine uptake from 25 μM lcarnitine solution in presence of 500 μM drug compared to lcarnitine uptake without drug present Hence the pharmacophore accurately prioritized compounds for testing K i measurements showed low micromolar inhibitors belonged to diverse therapeutic classes of drugs including many not previously known to inhibit hOCTN2 Compounds were more likely to cause rhabdomyolysis if the C max/K i ratio was higher than 00025This work was supported in part by National Institutes of Health grant DK67530 The authors kindly acknowledge Dr Xin Ming and Dr Dhiren R Thakker University of North CarolinaChapel Hill for providing the hOCTN2MDCK cell line used in this study The authors gratefully acknowledge Dr Matthew D Krasowski for his assistance in creating the SCUT 2008 database supplemented with metabolites and drugs of abuse The authors also thank Accelrys San Diego CA for making Discovery Studio Catalyst available
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