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Pharmacogenetic hSLCO1B1*14-Guided Dosing of Methotrexate in Transgenic Arthritic Mice Normalizes Exposure and

Felicia Gooden1,2, Brennan D Meier3, Griffin D Shaffer1,2

  • 1Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Clinical and Translational Science
|December 25, 2025
PubMed

Insights

Juvenile idiopathic arthritis patients with the SLCO1B1*14 allele show increased methotrexate clearance. Personalized dosing based on pharmacogenetics can improve methotrexate efficacy and tolerability in JIA.

Area of Science:

  • Pharmacogenomics
  • Immunology
  • Drug Metabolism

Background:

  • Juvenile idiopathic arthritis (JIA) affects ~100,000 children in the US, with ~30% failing methotrexate (MTX) therapy.
  • The SLCO1B1*14 allele is linked to increased MTX clearance, reduced exposure, and nonresponse in JIA patients.
  • Understanding genetic influences on MTX pharmacokinetics is crucial for optimizing JIA treatment.

Purpose of the Study:

  • To investigate the impact of the SLCO1B1*14 allele on MTX response in a mouse model of JIA.
  • To assess the potential of pharmacogenetic-guided dosing to improve MTX efficacy in JIA.

Main Methods:

  • Generated transgenic mice expressing human SLCO1B1*14 and control hSLCO1B1*1 alleles, with mSlco1b2 knocked out.
  • Utilized a collagen-induced arthritis model to assess arthritic response to MTX.
  • Employed mass spectrometry-based proteomics and pharmacokinetic modeling to analyze OATP1B1 abundance and MTX exposure.

Main Results:

  • hSLCO1B1*14 mice exhibited 2.1-fold higher OATP1B1 protein abundance compared to hSLCO1B1*1 mice.
  • Treatment with 1 mg/kg MTX resulted in a 39% increase in disease burden and 22% reduced MTX AUC in hSLCO1B1*14 mice.
  • Pharmacokinetic modeling indicated a 30% higher MTX dose needed in hSLCO1B1*14 mice to match exposure and response of hSLCO1B1*1 mice.

Conclusions:

  • The SLCO1B1*14 allele significantly increases MTX clearance and reduces therapeutic efficacy in a JIA mouse model.
  • Pharmacogenetic-guided dosing, such as increasing MTX dose by 30% in carriers of the SLCO1B1*14 allele, can normalize MTX exposure and response.
  • These findings support the clinical utility of pharmacogenetic testing for optimizing MTX treatment in JIA patients.

Keywords:
animal/mouse/rodentmodelingpharmacogeneticspharmacokineticspreclinicalsimulationtranslational pharmacology

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