Abstract
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.
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Acknowledgements
This work was partially supported by grant 756 GM068885-05 from the NIGMS awarded to GP. We thank Michael Soth and Adrian Fretland for valuable discussions and Zhaomei Zhang, Hoangdung Ho, Erin Farrell, Wendy Klopf, and Olga Vilenski for reviewing the manuscript.
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The manuscript has not been published elsewhere, nor is it being evaluated for publication elsewhere. Several authors are employees of Roche Palo Alto, but there are no other conflicts of interest around this manuscript.
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Zhang, X., Liu, HH., Weller, P. et al. In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor. Pharmacogenomics J 11, 15–24 (2011). https://doi.org/10.1038/tpj.2010.8
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DOI: https://doi.org/10.1038/tpj.2010.8
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