What is the Difference Between Methotrexate and Leflunomide

The key difference between methotrexate and leflunomide is that methotrexate is a chemotherapeutic agent that antagonizes folate to inhibit the synthesis of DNA and RNA, while leflunomide is a prodrug that suppresses the immune system by blocking pyrimidine-mediated DNA and RNA synthesis after metabolizing into A77 1726.

Methotrexate and leflunomide are two medications used to treat rheumatoid arthritis and psoriatic arthritis. Both these drugs belong to the drug class of disease-modifying antirheumatic drugs. Methotrexate is a folate antagonist that blocks cell division by preventing the synthesis of DNA and RNA. Leflunomide is a prodrug metabolized in the liver to its active form, A77 1726. The active leflunomide blocks the de novo pyrimidine synthesis and thereby prevents DNA and RNA synthesis, which will ultimately result in the inhibition of immune cell growth. Both these drugs are absorbed by the gastrointestinal tract after oral administration and distributed through the body by binding with plasma proteins, including albumin. Leflunomide is a relatively fast-acting drug, while leflunomide is a relatively slow-acting drug. The choice between methotrexate and leflunomide depends on the patient’s features, such as age, gender, other medical conditions, and preferences.

CONTENTS

1. Overview and Key Difference
2. What is Methotrexate 
3. What is Leflunomide
4. Similarities – Methotrexate and Leflunomide
5. Methotrexate vs Leflunomide in Tabular Form
6. Summary – Methotrexate vs Leflunomide

What is Methotrexate?

Methotrexate is a chemotherapeutic agent and immune system suppressant in the disease-modifying antirheumatic drug class. It primarily treats cancers, autoimmune diseases, and ectopic pregnancies by blocking cell division. Methotrexate is a folate antagonist, suggesting that it blocks the action of folate. Folate is a vitamin needed for cell division. Methotrexate specifically targets dihydrofolate reductase, an enzyme essential for converting folate into its active form, tetrahydrofolate. Tetrahydrofolate is then used to form DNA and RNA, which are the building blocks of cells. Therefore, blocking the dihydrofolate reductase by methotrexate prevents the cells from making DNA and RNA, leading to cell death.

Methotrexate is a powerful medication with serious side effects. The most common side effects include nausea, vomiting, diarrhea, mouth sores, fatigue, and hair loss. The most severe side effects include liver, kidney, and bone marrow suppression. Methotrexate is well absorbed from the gastrointestinal tract after oral administration. The bioavailability of oral methotrexate is typically around 70%. The drug is widely distributed and highly bound with plasma proteins such as albumin. Methotrexate is metabolized in the liver and primarily excreted by the kidneys with an elimination half-life of 6 hours.

What is Leflunomide?

Leflunomide is another member of the disease-modifying antirheumatic drug class, which suppresses the immune system by blocking the production of pyrimidines. Pyrimidines are the building blocks of DNA and RNA. The drug primarily treats chronic inflammatory diseases like rheumatoid arthritis and psoriatic arthritis. The active metabolites of leflunomide, A77 1726, inhibit dihydroorotate dehydrogenase, an essential enzyme for the de novo synthesis of pyrimidines. Leflunomide hinders dihydroorotate dehydrogenase activity, ultimately impeding the development of immune cells, such as B and T cells. Leflunomide is a relatively slow-acting drug with relatively 4-6 weeks of onset of action. The drug is well-tolerated but can cause side effects such as diarrhea, nausea, vomiting, and liver problems.

Leflunomide is a prodrug that is absorbed well from the gastrointestinal tract after oral administration, and the bioavailability is typically around 80% after oral administration. The drug is then distributed through the body after binding with plasma proteins like albumin. Leflunomide is then primarily metabolized by the liver into its active form A77 1726, and then the metabolite is eliminated by renal and direct biliary excretion.

What are the Similarities Between Methotrexate and Leflunomide?

• Methotrexate and leflunomide belong to a similar drug class of disease-modifying antirheumatic drugs.
• Both these medications are effective in treating rheumatoid arthritis and psoriatic arthritis.
• They share common side effects, such as nausea, vomiting, and diarrhea.
• Both medications should be monitored closely for serious side effects.

What is the Difference Between Methotrexate and Leflunomide?

Methotrexate and leflunomide are medications used to treat rheumatoid arthritis and psoriatic arthritis. They both belong to the drug class of disease-modifying antirheumatic drugs but differ in various ways. Methotrexate works by blocking cell division and preventing the synthesis of DNA and RNA as folate antagonists. On the other hand, leflunomide is a prodrug that is metabolized in the liver to its active form, A77 1726. Thus, this is the key difference between methotrexate and leflunomide.

The active leflunomide blocks the de novo pyrimidine synthesis, which ultimately inhibits immune cell growth by preventing DNA and RNA synthesis. During their mechanism of action, methotrexate and leflunomide inhibit dihydrofolate reductase and dihydroorotate dehydrogenase, respectively. Compared to leflunomide, methotrexate is a relatively fast-acting drug and is typically taken once a week. Methotrexate has more side effects than leflunomide and requires more frequent monitoring by a healthcare provider.

The infographic below presents the differences between methotrexate and leflunomide in tabular form for side-by-side comparison.

Summary – Methotrexate vs Leflunomide

To treat rheumatoid arthritis and psoriatic arthritis, medications like methotrexate and leflunomide are often prescribed. While they belong to the same drug class of disease-modifying antirheumatic drugs, they have different mechanisms of action. Methotrexate blocks cell division and prevents DNA and RNA synthesis by acting as a folate antagonist. Leflunomide, on the other hand, is a prodrug that is metabolized in the liver to its active form, A77 1726, which blocks the de novo pyrimidine synthesis. This ultimately inhibits immune cell growth by preventing DNA and RNA synthesis. Both drugs inhibit different enzymes, with methotrexate inhibiting dihydrofolate reductase and leflunomide inhibiting dihydroorotate dehydrogenase. Methotrexate is generally faster-acting and is taken once a week, but it has more side effects and requires more frequent monitoring by a healthcare provider. So, this is the summary of the difference between methotrexate and leflunomide. When choosing a medication, individual patient factors such as age, gender, existing medical conditions, and personal preferences should be considered.

Reference:

1. Chan, Edwin S., and Bruce N. Cronstein. “Methotrexate—How Does It Really Work?” Nature Reviews Rheumatology, vol. 6, no. 3, 2010, pp. 175–178.
2. Breedveld, F C. “Leflunomide: Mode of Action in the Treatment of Rheumatoid Arthritis.” Annals of the Rheumatic Diseases, vol. 59, no. 11, 2000, pp. 841–849.

Image Courtesy:

1. “Methotrexate skeletal” By Yikrazuul – Own work (Public Domain) via Commons Wikimedia
2. “Leflunomide” By Fvasconcellos (talk · contribs) – Own work, after Sweetman, Sean C., ed (2009). Martindale: The complete drug reference (36th ed.). London: Pharmaceutical Press. p. 75. ISBN 978-0-85369-840-1. (Public Domain) via Commons Wikimedia