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What Is Methotrexate Toxicity?

By S. Berger
Updated May 17, 2024
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Methotrexate is a medication that is used to treat several medical conditions, including cancer and some autoimmune disorders. This drug is highly effective at controlling these conditions, but can cause toxic side effects. Depending on the route of administration into the body, as well as the dosage, methotrexate toxicity can vary widely.

The reason for potential methotrexate toxicity is connected to how this drug works in the body. It inhibits the action of certain proteins that create the compound folate, required for making proteins and deoxyribonucleic acid (DNA). By preventing the formation of DNA, it can prevent the replication of cancerous cells. Other cells that replicate can also be affected by this drug, however, including bone marrow and gastrointestinal (GI) tract cells.

Common side effects caused by methotrexate toxicity are usually related to tissue with frequently dividing cells. Mouth sores, GI distress, nausea, and lowered counts of white blood cells are often seen with this medication. Bone marrow, liver, and kidney tissue can all be damaged over time with repeated dosages of methotrexate, so many treatment regimens involve frequent testing of these tissues to ensure that irreversible damage is not being caused.

Acute methotrexate toxicity may underlie some side effects of this drug. Medical attention should be immediately sought in the event of bloody stools, bloody urine, calf pain, or bone pain. Allergic reactions that involve swelling or shortness of breath are also reasons to seek medical assistance. This toxicity can be treated with the administration of substances like thymidine and leucovorin, but early detection of tissue damage gives the best prognosis for recovery.

Patients that already have lowered blood cell counts should not take this drug, because bone marrow damage is usually the primary form of methotrexate toxicity. Doctors will often run tests to determine whether blood cell levels are staying in acceptable ranges. Folate therapy, involving taking folate or folic acid supplements, can sometimes mitigate this toxicity.

The potential toxicity from this drug depends, to some extent, on how it is administered. Oral usage allows the medication to reach most of the tissue in the body, and, as such, leads to the maximum levels of toxic side effects. Intravenous (IV) injection also allows for a wide distribution of this medication, but with fewer GI side effects than those seen with oral use. Intrathecal administration, or injection into the spinal fluid, keeps the action of the drug localized to a small area, and thus, causes a minimal amount of side effects.

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