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Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype

H Gurney1, M Wong, R L Balleine

  • 1Department of Medical Oncology, Westmead Hospital Sydney West Area Health Service, Westmead, New South Wales, Australia. howard_gurney@wmi.usyd.edu.au

Clinical Pharmacology and Therapeutics
|May 15, 2007
PubMed

Insights

Individual differences in drug elimination affect imatinib levels. The ABCB1 gene influences imatinib clearance and steady-state concentrations, potentially reducing dose adjustments for certain patients.

Area of Science:

  • Pharmacology
  • Genetics
  • Oncology

Background:

  • Imatinib is a crucial targeted therapy for gastrointestinal stromal tumors (GIST) and chronic myeloid leukemia (CML).
  • Individual variability in drug metabolism and transport significantly impacts imatinib efficacy and toxicity.
  • Understanding genetic factors influencing imatinib disposition is essential for personalized treatment strategies.

Purpose of the Study:

  • To investigate the influence of genetic variations, specifically in CYP3A5 and ABCB1 genes, on imatinib pharmacokinetics.
  • To determine the relationship between elimination phenotype, single-nucleotide polymorphisms (SNPs), and imatinib clearance (CL/F).
  • To assess the impact of ABCB1 genotype on imatinib disposition at both initial dosing and steady-state.

Main Methods:

  • Pharmacokinetic analysis of imatinib in 22 patients with GIST or CML.
  • Comparison of pharmacokinetic parameters (CL/F) on day 1 and at steady-state.
  • Genotyping for CYP3A5 and ABCB1 (1236T>C, 2677G>T/A, 3435C>T loci) single-nucleotide polymorphisms.
  • Correlation of genetic data with observed elimination phenotypes and drug clearance.

Main Results:

  • A fivefold variation in imatinib CL/F was observed on day 1.
  • Mean CL/F decreased by 26% at steady-state compared to day 1.
  • Reduced imatinib CL/F at steady-state was significantly associated with specific ABCB1 genotypes (thymidine homozygotes at tested loci).
  • Toxicity-related dose reductions were less frequent in patients with these ABCB1 genotypes.

Conclusions:

  • ABCB1 genotype plays a significant role in determining steady-state imatinib CL/F.
  • The observed genotype-specific influence of imatinib on elimination warrants further investigation.
  • Consideration of ABCB1 genotype may aid in optimizing imatinib dosage and minimizing toxicity in cancer patients.

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