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Methotrexate Metabolism and Its Relation to Clinical Effects: A Primer

  • Authors: Author: Joel M. Kremer, MD
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Target Audience and Goal Statement

This activity is intended for rheumatologists and oncologists.

The goal of this activity is to educate physicians who use methotrexate in their patients about the metabolic pathways and influences on metabolism of methotrexate.

Upon completion of this activity, participants will be able to:

  1. List possible genetic variations in methotrexate metabolism.
  2. Enumerate influences of diet on methotrexate metabolism.
  3. Discuss the influence of metabolism of methotrexate on its efficacy and toxicity in rheumatic and oncologic diseases.


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  • Joel M. Kremer, MD

    Director of Research, The Center for Rheumatology, Clinical Professor of Medicine, Albany Medical College, Albany, New York; Director of Research, Albany Medical Center Hospital, Albany, New York


    Disclosure: Joel M. Kremer, MD, has disclosed that he has received grant support and served as a consultant for Prometheus, Amgen, Abbott, Aventis, Centocor, and Merck. Dr. Kremer has disclosed that he discusses the unlabeled or investigational use of allopurinol to ameliorate methotrexate toxicity in this activity.

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Methotrexate Metabolism and Its Relation to Clinical Effects: A Primer

Authors: Author: Joel M. Kremer, MDFaculty and Disclosures


Substantial portions of this article are reproduced with permission of John Wiley & Sons, Inc. from: Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum. 2004;50:1370-1382. Copyright © 2004, American College of Rheumatology.


In the 55 years since Farber[1] first described clinical remissions after use of the folate antagonist aminopterin for children with acute leukemia, methotrexate (MTX) has been used to treat millions of patients with both malignant and autoimmune diseases.[2] MTX is now the most widely prescribed disease-modifying antirheumatic drug (DMARD), used by at least 500,000 patients worldwide with rheumatoid arthritis. MTX is prescribed for more patients with rheumatoid arthritis than all of the biologic drugs in current use combined. It is the most commonly reported agent used in combination with other DMARDs, where clear additive therapeutic value is demonstrated.[2,3-9] The fear of severe organ-associated toxicity has abated with the development of guidelines for monitoring liver toxicity,[10] which has resulted in the virtual elimination of this problem, which had so frightened physicians and limited its earlier use. In addition, the recognition that MTX-associated pulmonary disease is most often a subacute syndrome associated with dry cough, often with dyspnea and fever,[11,12] has led to earlier recognition and avoidance of permanent lung sequelae in many patients receiving the drug. The realization that many of the gastrointestinal, bone marrow, and other toxicities, which so frequently limited its use prior to the 1980s, could be avoided by the routine use of folate supplementation,[13,14] has also given both clinicians and patients a heightened measure of security when prescribing this potent antimetabolite.

However, the overall level of sophistication regarding the many issues and complexities associated with the use of MTX is still often somewhat low. Many clinicians employ folic acid or folinic acid interchangeably without knowledge of differences in effects, while others may use MTX with a variety of other drugs in patients who may be at increased risk of adverse events due to significant drug interactions. Ideas and prescribing patterns associated with maximum weekly doses, use in the elderly, monitoring of blood tests, and when to "give up" and add other agents to be prescribed with MTX are often followed without specific rigorous scientific support.

It is apparent that very busy clinicians often do not have the time or resources to research and understand every publication describing the optimal, and sometimes subtle, mechanistic pathways that potentially can be used to support clinical decisions regarding the use of an agent like MTX.

It is the goal of this Clinical Update to review the major and significant relevant metabolic concepts associated with the use of MTX in patients with rheumatic disease, rather than to summarize publications of its clinical effects. A great deal of what we have learned about the metabolism of MTX is derived from the oncology literature, which is the source of a very large number of significant insights that are relevant to the manner in which rheumatologists use the drug in the treatment of rheumatic disease. Clinicians who are able to improve their familiarity with the metabolic, pharmacologic, and pharmacokinetic concepts presented should be better able to use the drug in a safer and more effective manner. It will also be seen that a newly emerging ability to routinely measure the effects of MTX on intracellular metabolites holds promise for predicting both efficacy and toxicity.