Document Type
Article
Publication Date
1-2026
Identifier
DOI: 10.1111/cts.70449; PMCID: PMC12739525
Abstract
Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease that negatively affects ~100,000 children under the age of 16 in the United States. About ~30% of these patients fail first-line drug therapy with low-dose methotrexate (MTX) due to poor tolerability or lack of efficacy. The SLCO1B1*14 allele is associated with increased MTX clearance and has been linked to reduced overall drug exposure and nonresponse to MTX in JIA patients. Herein, we describe transgenic hSLCO1B1*14 and hSLCO1B1*1 DBA1/J mSlco1b2 knock-out mice, which we used to assess arthritic response to MTX using the collagen-induced arthritis model. Mass spectrometry-based proteomics analysis revealed that OATP1B1 protein abundance was 2.1-fold higher in hSLCO1B1*14 mice compared to hSLCO1B1*1 mice. Following treatment with 1 mg/kg MTX for 3 weeks, hSLCO1B1*14 mice exhibited a 39% increase in median arthritic disease burden (p = 0.02) and a 22% reduction in MTX AUC (p = 0.14) compared to hSLCO1B1*1 mice. Pharmacokinetic modeling estimated that the hSLCO1B1*14 mice would need a 30% higher dose to equalize exposure and response to hSLCO1B1*1 mice. When hSLCO1B1*14 mice received 1.3 mg/kg MTX, the arthritic disease burden and overall MTX exposure were less than the 1 mg/kg MTX in hSLCO1B1*1 mice, reinforcing that differences in MTX elimination and therapeutic response can be accounted for by using pharmacogenetic-guided dosing of MTX in JIA patients.
Journal Title
Clin Transl Sci
Volume
19
Issue
1
First Page
70449
Last Page
70449
MeSH Keywords
Animals; Methotrexate; Mice; Arthritis, Experimental; Arthritis, Juvenile; Liver-Specific Organic Anion Transporter 1; Mice, Knockout; Humans; Disease Models, Animal; Mice, Transgenic; Male; Dose-Response Relationship, Drug; Antirheumatic Agents; Mice, Inbred DBA; Female
PubMed ID
41445524
Keywords
animal/mouse/rodent; modeling; pharmacogenetics; pharmacokinetics; preclinical; simulation; translational pharmacology
Recommended Citation
Gooden F, Meier BD, Shaffer GD, et al. Pharmacogenetic hSLCO1B1*14-Guided Dosing of Methotrexate in Transgenic Arthritic Mice Normalizes Exposure and Response. Clin Transl Sci. 2026;19(1):e70449. doi:10.1111/cts.70449
Comments
Grants and funding
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Publisher's Link: https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.70449