In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor
作者： X Zhang , H-H Liu , P Weller , M Zheng , W Tao
DOI: 10.1038/TPJ.2010.8
关键词:
摘要: The clinical development of a candidate p38 kinase inhibitor was terminated because its unexpectedly rapid clearance in human subjects. Its short half-life and metabolic profile beings were vastly different from that rats, dogs, monkeys characterized during routine pre-clinical studies. Mice generated the predominant drug (4-hydroxylated) metabolite produced beings, which not found other species. data murine vitro biotransformation assay used liver extracts 14 inbred mouse strains analyzed by haplotype-based computational genetic analysis. This led to identification aldehyde oxidase-1 (AOX1) as enzyme responsible for metabolism this drug. Specific inhibitors expressed recombinant enzymes confirm AOX catalyzed formation 4-hydroxylated man. Genetic variation within Aox1 regulated level hepatic mRNA, AOX1 protein, activity among strains. Thus, pharmacogenetic analysis can facilitate characterization pathways are differentially utilized humans
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