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Predicting Intrinsic Clearance for Drugs and Drug Candidates Metabolized by Aldehyde Oxidase

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Department of Chemistry, Washington State University, Pullman, Washington 99163, United States
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States
*Tel: 509-592-8790. E-mail: [email protected]
Cite this: Mol. Pharmaceutics 2013, 10, 4, 1262–1268
Publication Date (Web):January 30, 2013
Copyright © 2013 American Chemical Society

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    Metabolism by aldehyde oxidase (AO) has been responsible for a number of drug failures in clinical trials. The main reason is the clearance values for drugs metabolized by AO are underestimated by allometric scaling from preclinical species. Furthermore, in vitro human data also underestimates clearance. We have developed the first in silico models to predict both in vitro and in vivo human intrinsic clearance for 8 drugs with just two chemical descriptors. These models explain a large amount of the variance in the data using two computational estimates of the electronic and steric features of the reaction. The in vivo computational models for human metabolism are better than in vitro preclinical animal testing at predicting human intrinsic clearance. Thus, it appears that AO is amenable to computational prediction of rates, which may be used to guide drug discovery, and predict pharmacokinetics for clinical trials.

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