Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance

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Y Tanaka1, A Manabe2, H Fukushima3

  • 1Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan.

The Pharmacogenomics Journal
|November 19, 2014
PubMed

Insights

Multidrug resistance protein 4 (MRP4) genetic variations impact 6-mercaptopurine (6-MP) dosing in Japanese children with acute lymphoblastic leukemia (ALL). MRP4 genotyping can personalize 6-MP therapy during ALL maintenance.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Genetics

Background:

  • Multidrug resistance protein 4 (MRP4) influences drug sensitivity by mediating nucleoside derivative efflux.
  • Understanding genetic variations in MRP4 is crucial for optimizing chemotherapy in pediatric acute lymphoblastic leukemia (ALL).

Purpose of the Study:

  • To investigate the association between MRP4 genetic polymorphisms and 6-mercaptopurine (6-MP) and methotrexate doses in Japanese children with ALL.
  • To evaluate the frequency of therapeutic interruptions during maintenance therapy based on MRP4 genotypes.

Main Methods:

  • Analysis of 94 Japanese pediatric ALL patients receiving 6-MP doses (30-50 mg/m²).
  • Genotyping for MRP4 polymorphisms (G2269A, C912A, G559T) and inosine triphosphate pyrophosphatase.
  • Comparison of 6-MP dose requirements and therapeutic interruption frequency between patients with different genotypes.

Main Results:

  • Patients with homozygous variant alleles in MRP4 (G2269A, C912A, G559T) required more frequent 6-MP dose reductions.
  • The average 6-MP dose was significantly lower for patients with homozygous variant alleles in MRP4 or inosine triphosphate pyrophosphatase during maintenance therapy (30.5 vs. 40.0 mg/m²).

Conclusions:

  • MRP4 genetic polymorphisms are associated with altered 6-MP dosage requirements in Japanese pediatric ALL patients.
  • MRP4 genotyping may facilitate personalized 6-MP therapeutic dosing strategies during ALL maintenance therapy.

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