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A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469

Jacqueline Ramírez1, Tae Won Kim, Wanqing Liu

  • 1aDepartment of Medicine, The University of Chicago, Chicago, Illinois bDepartment of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, USA.

Pharmacogenetics and Genomics
|December 5, 2013
PubMed

Insights

Genetic variations in aldehyde oxidase I (AOX1) were investigated for their impact on XK469 drug clearance. Despite some associations, AOX1 polymorphisms do not explain the variability in XK469 clearance across patients.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Oncology

Background:

  • XK469 is a topoisomerase II β inhibitor primarily metabolized by aldehyde oxidase I (AOX1).
  • Interindividual variability in drug clearance can be influenced by genetic factors.

Purpose of the Study:

  • To investigate the association between genetic variations in AOX1 and interindividual differences in XK469 clearance.
  • To determine if AOX1 single nucleotide polymorphisms (SNPs) contribute to XK469 pharmacokinetics.

Main Methods:

  • A candidate gene study was conducted in White patients with advanced refractory solid tumors and leukemia.
  • Genotyping of 41 AOX1 SNPs and seven liver expression quantitative trait loci.
  • Analysis of XK469 clearance in relation to identified genetic markers.

Main Results:

  • A significant decrease in XK469 clearance was observed in solid tumor patients with the rs10931910 SNP (τ=-0.32, P=0.003), but this finding was not replicated in the leukemia cohort.
  • Four other AOX1 SNPs showed associations with clearance in only one of the two patient cohorts (P=0.01-0.02).

Conclusions:

  • The study suggests that polymorphisms in AOX1 are unlikely to be the primary drivers of variability in XK469 clearance.
  • Further research is needed to explore the functional significance of AOX1 SNPs in drug metabolism.
  • This study serves as a foundation for future investigations into AOX1's role in XK469 pharmacokinetics.

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