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Molecular mechanism of action and pharmacokinetic properties of methotrexate

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Abstract

Since its discovery in 1945, methotrexate has become a standard therapy for number of diseases, including oncological, inflammatory and pulmonary ones. Major physiological interactions of methotrexate include folate pathway, adenosine, prostaglandins, leukotrienes and cytokines. Methotrexate is used in treatment of pulmonary sarcoidosis as a second line therapy and is drug of choice in patients who are not candidates for corticosteroid therapy, with recommended starting weekly dose of 5–15 mg. Number of studies dealt with methotrexate use in rheumatoid arthritis and oncological patients. Authors are conducting research on oral methotrexate use and pharmacokinetics in chronic sarcoidosis patients and have performed literature research to better understand molecular mechanisms of methotrexate action as well as high level pharmacokinetic considerations. Polyglutamation of methotrexate affects its pharmacokinetic and pharmacodynamic properties and prolongs its effect. Bile excretion plays significant role due to extensive enterohepatic recirculation, although majority of methotrexate is excreted through urine. Better understanding of its pharmacokinetic properties in sarcoidosis patients warrant optimizing therapy when corticosteroids are contraindicated in these patients.

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Abbreviations

γGH:

γ-Glutamate hydrolase

7-OH-MTX:

7-Hydroxy-MTX

ADP:

Adenosine diphosphate

AICAR:

5-Aminoimidazole-4-carboxamide ribonucleoside

AO:

Aldehyde oxidase

ATIC:

AICAR transformylase

ATP:

Adenosine triphosphate

COX:

Cyclooxygenase

DAMPA:

4-Amino-deoxy-N10-methylpteroic acid

DHF:

Dihydrofolate

DHFR:

Dihydrofolate reductase

dTMP:

2-Deoxythymidine-5-monophosphate

dUMP:

2-Deoxyuridine-5-monophosphate

Ecto5′NT:

Ecto-5′-nucleotidase

ENTPD:

Ectonucleoside triphosphate diphosphohydrolase

GAR:

Glycinamide ribonucleotide

GART:

GAR transaminase

IL-1:

Interleukin-1

IL-1β:

Interleukin-1β

MTX:

Methotrexate

NF-kB:

Nuclear factor kapa-B

PGE2:

Prostaglandin E2

RA:

Rheumatoid arthritis

RP-HPLC:

Reversed phase high performance liquid chromatography

THF:

Tetrahydrofolate

TLR:

Toll-like receptors

TNF-α:

Tumor necrosis factor alfa

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Funding

This research was supported by HORIZON2020 MEDLEM Project No. 690876 and the Project for Scientific and Technological Development of Vojvodina No. 114-451-2072/2016-02.

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Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000, Novi Sad, Serbia

    V. Maksimovic, S. Vukmirovic & M. Mikov

  2. Institute of Pulmonary Diseases, Sremska Kamenica, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia

    Z. Pavlovic-Popovic

  3. Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia

    J. Cvejic & S. Golocorbin-Kon

  4. Biotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia

    A. Mooranian & H. Al-Salami

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  1. V. Maksimovic
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  2. Z. Pavlovic-Popovic
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  3. S. Vukmirovic
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  4. J. Cvejic
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  5. A. Mooranian
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  6. H. Al-Salami
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Correspondence to V. Maksimovic.

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Maksimovic, V., Pavlovic-Popovic, Z., Vukmirovic, S. et al. Molecular mechanism of action and pharmacokinetic properties of methotrexate. Mol Biol Rep 47, 4699–4708 (2020). https://doi.org/10.1007/s11033-020-05481-9

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