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

Pharmacogenomics J. 2011 Feb;11(1):15-24. doi: 10.1038/tpj.2010.8. Epub 2010 Feb 23.


The clinical development of a candidate p38 kinase inhibitor was terminated because of its unexpectedly rapid clearance in human subjects. Its short half-life and metabolic profile in human beings were vastly different from that in rats, dogs, and monkeys characterized during routine pre-clinical studies. Mice generated the predominant drug (4-hydroxylated) metabolite produced in human beings, which was not found in other species. The data from a murine in vitro drug biotransformation assay that used liver extracts from 14 inbred mouse strains were analyzed by haplotype-based computational genetic analysis. This led to the identification of aldehyde oxidase-1 (AOX1) as the enzyme responsible for the rapid metabolism of this drug. Specific enzyme inhibitors and expressed recombinant enzymes were used to confirm that AOX catalyzed the formation of the 4-hydroxylated drug metabolite in mouse and man. Genetic variation within Aox1 regulated the level of hepatic Aox1 mRNA, AOX1 protein, and enzyme activity among the inbred strains. Thus, computational murine pharmacogenetic analysis can facilitate the identification and characterization of drug metabolism pathways that are differentially utilized by humans and other species.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aldehyde Oxidase / biosynthesis
  • Aldehyde Oxidase / genetics
  • Aldehyde Oxidase / metabolism*
  • Animals
  • Arthritis, Rheumatoid / drug therapy
  • Dogs
  • Female
  • Half-Life
  • Haplorhini
  • Humans
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred Strains
  • Pharmacogenetics / methods*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidinones / pharmacology
  • Rats
  • Rats, Inbred BB
  • Single-Blind Method
  • Species Specificity
  • Young Adult
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Protein Kinase Inhibitors
  • Pyrimidinones
  • AOX1 protein, human
  • Aldehyde Oxidase
  • Aox1 protein, mouse
  • p38 Mitogen-Activated Protein Kinases