Methotrexate disposition, anti-folate activity and efficacy in the collagen-induced arthritis mouse model

Singh, Rakesh K.; Haandel, Leon van; Kiptoo, Paul; Becker, Mara L.; Siahaan, Teruna J.; Funk, Ryan S.

doi:10.1016/j.ejphar.2019.03.052

Cited by 19 publications

(30 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In particular, several markers of pyrimidine and purine biosynthesis, including deoxyuridine monophosphate, 2‐deoxycytidine, 2‐deoxyuridine, and IMP may represent highly sensitive markers of MTX activity. These findings are consistent with previous studies that have found MTX treatment is associated with systemic depletion of circulating folates and corresponding dysregulation of intermediates of nucleotide metabolism …”

Section: Discussionsupporting

confidence: 93%

“…These findings are consistent with previous studies that have found MTX treatment is associated with systemic depletion of circulating folates and corresponding dysregulation of intermediates of nucleotide metabolism. 18,28,29,41 Additional metabolites outside of folate and nucleotide metabolism displayed a high sensitivity to MTX. These metabolites included a metabolic intermediate of valine metabolism (i.e., ketoisovaleric acid) and several sugars, including galactose and fructose.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Metabolomic Profiling to Identify Molecular Biomarkers of Cellular Response to Methotrexate In Vitro

Funk

Singh

Becker

2019

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

Variation in methotrexate (MTX) efficacy represents a significant barrier to early and effective disease control in the treatment of autoimmune arthritis. We hypothesize that the utilization of metabolomic techniques will allow for an improved understanding of the biochemical basis for the pharmacological activity of MTX, and can promote the identification and evaluation of novel molecular biomarkers of MTX response. In this work, erythroblastoid cells were exposed to MTX at the physiologic concentration of 1,000 nM and analyzed using three metabolomic platforms to give a broad spectrum of cellular metabolites. MTX pharmacological activity, defined as cellular growth inhibition, was associated with an altered cellular metabolomic profile based on the analysis of 724 identified metabolites. By discriminant analysis, MTX treatment was associated with increases in ketoisovaleric acid, fructose, galactose, and 2‐deoxycytidine, and corresponding reductions in 2‐deoxyuridine, phosphatidylinositol 32:0, orotic acid, and inosine monophosphate. Inclusion of data from analysis of folate metabolism in combination with chemometric and metabolic network analysis demonstrated that MTX treatment is associated with dysregulated folate metabolism and nucleotide biosynthesis, which is in line with its known mechanism of action. However, MTX treatment was also associated with alterations in a diversity of metabolites, including intermediates of amino acid, carbohydrate, and lipid metabolism. Collectively, these findings support a robust metabolic response following exposure to physiologic concentrations of MTX. They also identify various metabolic intermediates that are associated with the pharmacological activity of MTX, and are, therefore, potential molecular biomarker candidates in future preclinical and clinical studies of MTX efficacy in autoimmune arthritis.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling to Identify Molecular Biomarkers of Cellular Response to Methotrexate In Vitro

Funk

Singh

Becker

2019

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

show abstract

“… 5 , 15 These polymorphisms are challenging to study in a murine model given that a universal knockout of Rfc1 results in embryonic death 49 and DBA/1J mice are deficient in the formation of MTX polyglutamates. 50 Currently, there is an ongoing clinical trial by the CARRA Group (PROMOTE) to investigate PGx variant genomewide associations with MTX polyglutamates, toxicity, and therapeutic outcomes in patients with JIA; this work could provide additional support for examining the effect of variation in SLCO1B1 and several key PGx genes of interest on MTX response and toxicity in adults with RA or patients with other autoimmune diseases that are treated with low‐dose MTX (e.g., inflammatory bowel disease and psoriasis).…”

Section: Discussionmentioning

confidence: 99%

Toward pharmacogenetic SLCO1B1‐guided dosing of methotrexate in arthritis using a murine Slco1b2 knockout model

Taylor

Thompson

Bear

et al. 2021

Clinical Translational Sci

View full text Add to dashboard Cite

Low-dose methotrexate (MTX) is a first-line therapy for the treatment of arthritis. However, there is considerable inter-individual variability in MTX exposure following standard dosing. Polymorphisms in SLCO1B1 significantly effect MTX clearance, altering therapeutic response. One decreased function variant, rs4149056 (c.521T>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, Slco1b2. Our objective was to investigate the impact of this phenotype on the pharmacokinetics and therapeutic outcomes of low-dose MTX in a murine model of collagen-induced arthritis (CIA). We evaluated response to MTX in mice with CIA using wildtype (WT), heterozygous, and KO Slco1b2 mice on a DBA1/J background. Arthritis was macroscopically evaluated daily to quantify disease progression. Mice received 2 mg/kg or a pharmacogenetically-guided MTX dose subcutaneously 3 times a week for 2 weeks. MTX concentrations were collected at the end of the study and exposure (day*µM) was estimated using a two-compartment model. Mice displayed a 7-fold range in MTX exposure and revealed a significant exposure-response relationship (p=0.0027). KO mice receiving the 2 mg/kg dosing regimen had 2.3-fold greater exposure to MTX (p<0.0001) and a 66% reduction in overall disease progression (p=0.011) compared to WT mice. However, exposure and response were equivalent when pharmacogenetically-guided dosing was used. These studies demonstrate that an exposure-response relationship exists for MTX and that Slco1b2 genotype affects MTX exposure and therapeutic response. Such evidence supports the use of SLCO1B1-pharmacogenetic dosing of low-dose methotrexate for patients with arthritis.

show abstract

“…Plasma MTX level is not a reliable predictor for adverse events in MTX therapy [ 132 ]. On the contrary, circulating folate levels and folate polyglutamate distribution change sensitively with MTX exposure and exogenous folate supply [ 133 ] and could be used as a biomarker of MTX efficacy [ 107 ]. It should be noted that as erythrocytes have a half-life of approximately 120 days, the results of blood examinations might reflect both pretreatment and posttreatment status, which need to be analyzed carefully [ 99 ].…”

Section: Discussionmentioning

confidence: 99%

A Review of Clinical Applications and Side Effects of Methotrexate in Ophthalmology

Wang

Peng

2020

Journal of Ophthalmology

View full text Add to dashboard Cite

Methotrexate (MTX) is a folate analog widely used against a range of diseases including malignancies and autoimmune disorders. Its high effectiveness-price ratio also won extensive application in ophthalmology. On the other hand, although MTX has an excellent pharmacological efficacy, MTX associated side effects in clinical use, which vary from patient to patient, are nonnegligible. There is no comparatively systematic review on MTX associated side effects and its risk factors. This review aimed to reveal novel clinical approaches of MTX and its adverse effects in order to provide a reference for ophthalmic scholars in clinical application of MTX.

show abstract

Methotrexate disposition, anti-folate activity and efficacy in the collagen-induced arthritis mouse model

Cited by 19 publications

References 57 publications

Metabolomic Profiling to Identify Molecular Biomarkers of Cellular Response to Methotrexate In Vitro

Metabolomic Profiling to Identify Molecular Biomarkers of Cellular Response to Methotrexate In Vitro

Toward pharmacogenetic SLCO1B1‐guided dosing of methotrexate in arthritis using a murine Slco1b2 knockout model

A Review of Clinical Applications and Side Effects of Methotrexate in Ophthalmology

Contact Info

Product

Resources

About