Predicting intrinsic clearance for drugs and drug candidates metabolized by aldehyde oxidase

Jeffrey P Jones; Kenneth R Korzekwa

doi:10.1021/mp300568r

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Predicting intrinsic clearance for drugs and drug candidates metabolized by aldehyde oxidase

Journal article

Open access

Peer reviewed

Predicting intrinsic clearance for drugs and drug candidates metabolized by aldehyde oxidase

Jeffrey P Jones and Kenneth R Korzekwa

Molecular pharmaceutics, Vol.10(4), pp.1262-1268

04/01/2013

DOI: https://doi.org/10.1021/mp300568r

Handle:

https://hdl.handle.net/2376/100699

PMCID: PMC3615103

PMID: 23363487

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https://doi.org/10.1021/mp300568rView

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Abstract

Liver - enzymology

Models, Chemical

Pteridines - chemistry

Humans

Regression Analysis

Metalloproteins - chemistry

Aldehyde Oxidase - chemistry

Microsomes, Liver - drug effects

Computer Simulation

Drug Design

Oxygen - chemistry

Software

Coenzymes - chemistry

Drug Evaluation, Preclinical

Pharmacokinetics

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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Title: Predicting intrinsic clearance for drugs and drug candidates metabolized by aldehyde oxidase
Creators: Jeffrey P Jones - Department of Chemistry, Washington State University, Pullman, Washington 99163, USA. jpj@wsu.edu
Kenneth R Korzekwa
Publication Details: Molecular pharmaceutics, Vol.10(4), pp.1262-1268
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: R01 GM100874 / NIGMS NIH HHS GM100874 / NIGMS NIH HHS
Identifiers: 99900546519601842
Language: English
Resource Type: Journal article