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In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor

X Zhang1, H-H Liu, P Weller

  • 1Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, CA, USA.

The Pharmacogenomics Journal
|February 24, 2010
PubMed

Insights

Drug metabolism differs between species. Computational analysis in mice identified aldehyde oxidase-1 (AOX1) as key to rapid drug clearance in humans, aiding future drug development.

Area of Science:

  • Pharmacology
  • Genetics
  • Drug Metabolism

Background:

  • Clinical development of a p38 kinase inhibitor halted due to rapid human clearance.
  • Human metabolic profile differed significantly from pre-clinical animal models (rats, dogs, monkeys).
  • Mice produced a unique 4-hydroxylated metabolite not seen in other species.

Purpose of the Study:

  • Identify the enzyme responsible for rapid drug metabolism in humans.
  • Investigate species-specific drug biotransformation pathways.
  • Utilize computational pharmacogenetics for drug metabolism research.

Main Methods:

  • Analyzed murine in vitro drug biotransformation data using haplotype-based computational genetic analysis.
  • Utilized specific enzyme inhibitors and expressed recombinant enzymes for confirmation.
  • Examined genetic variation within Aox1 in 14 inbred mouse strains.

Main Results:

  • Identified aldehyde oxidase-1 (AOX1) as the enzyme responsible for rapid drug metabolism.
  • Confirmed AOX1 catalyzes the formation of the 4-hydroxylated metabolite in mouse and human.
  • Demonstrated genetic variation in Aox1 correlates with hepatic AOX1 mRNA, protein, and enzyme activity.

Conclusions:

  • Computational murine pharmacogenetics can identify species-specific drug metabolism pathways.
  • AOX1 plays a crucial role in the rapid metabolism of this p38 kinase inhibitor.
  • Findings facilitate understanding of interspecies differences in drug metabolism for improved drug development.

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