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Polymorphisms in <jats:italic>SLCO1B1<\/jats:italic> significantly effect MTX clearance, altering therapeutic response. One decreased function variant, rs4149056 (c.521T&gt;C, Val174Ala), slows MTX clearance and in vitro uptake of MTX. This phenotype was recapitulated in a mouse model using a knockout (KO) of the murine orthologue, <jats:italic>Slco1b2<\/jats:italic>. Our objective was to investigate the impact of this phenotype on the pharmacokinetics and therapeutic outcomes of low\u2010dose MTX in a murine model of collagen\u2010induced arthritis (CIA). We evaluated response to MTX in mice with CIA using wildtype (WT), heterozygous, and KO <jats:italic>Slco1b2<\/jats:italic> mice on a DBA1\/J background. Arthritis was macroscopically evaluated daily to quantify disease progression. Mice received 2\u00a0mg\/kg or a pharmacogenetically guided MTX dose subcutaneously 3 times a week for 2\u00a0weeks. MTX concentrations were collected at the end of the study and exposure (day*\u00b5M) was estimated using a two\u2010compartment model. Mice displayed a seven\u2010fold range in MTX exposure and revealed a significant exposure\u2010response relationship (<jats:italic>p<\/jats:italic> = 0.0027). KO mice receiving the 2\u00a0mg\/kg dosing regimen had 2.3\u2010fold greater exposure to MTX (<jats:italic>p<\/jats:italic> &lt; 0.0001) and a 66% reduction in overall disease progression (<jats:italic>p<\/jats:italic> = 0.011) compared to WT mice. However, exposure and response were equivalent when pharmacogenetically guided dosing was used. These studies demonstrate that an exposure\u2010response relationship exists for MTX and that <jats:italic>Slco1b2<\/jats:italic> genotype affects MTX exposure and therapeutic response. Such evidence supports the use of <jats:italic>SLCO1B1<\/jats:italic>\u2010pharmacogenetic dosing of low\u2010dose MTX for patients with arthritis.<\/jats:p>","DOI":"10.1111\/cts.13086","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T05:46:51Z","timestamp":1623649611000},"page":"2267-2277","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Toward pharmacogenetic <i>SLCO1B1<\/i>\u2010guided dosing of methotrexate in arthritis using a murine <i>Slco1b2<\/i> knockout model"],"prefix":"10.1111","volume":"14","author":[{"given":"Zachary L.","family":"Taylor","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Systems Physiology University of Cincinnati Cincinnati Ohio USA"},{"name":"Division of Research in Patient Services Cincinnati Children\u2019s Hospital Medical Center Cincinnati Ohio USA"},{"name":"Division of Clinical Pharmacology Cincinnati Children\u2019s Hospital Medical Center Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Bear","sequence":"additional","affiliation":[{"name":"Division of Research in Patient Services Cincinnati Children\u2019s Hospital Medical Center Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Cincinnati Children\u2019s Hospital Medical Center Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander 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