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Clinical Pharmacokinetics of Methotrexate

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Summary

The absorption of methotrexate following intramuscular injection and oral administration of small doses (>30mg/m2) is rapid and complete, whereas with oral doses in excess of 80mg/m2 absorption is less than complete. Pretreatment with oral neomycin decreases and with kanamycin increases the gastrointestinal absorption of oral methotrexate.

The plasma disposition of methotrexate is multiexponential. Due to differences in sampling schedule and assay methods, widely varying estimates of elimination half-life (tJ/2β of 6 to 69 hours of methotrexate have been reported. The long half-life may either be due to enterohepatic circulation of methotrexate and/or its metabolites or a slow elimination of dihydrofolate reductase (DHFR) bound methotrexate. The plasma clearance of methotrexate following small clinical doses is about 80ml/min, but may become saturated at high doses (20g). During high dose infusions, the peak plasma level is proportional to doses up to 200mg/kg.

Methotrexate is transported across cellular membranes via a carrier-mediated active type process. At high concentrations, when the carrier route is saturated, passive diffusion assumes greater importance.

Methotrexate is not highly bound to plasma proteins (∼50%). However, being highly ionised at physiological pH, the drug does not accumulate in the cerebrospinal fluid to any appreciable extent, necessitating intrathecal administration in the treatment of cerebral and meningeal metastases.

Renal excretion is the major route of elimination for methotrexate (∼80% ); the drug being actively secreted in the renal tubule by the general organic acid transport system. Hence, the renal clearance of methotrexate is decreased by the concomitant administration of organic acids, such as salicylate. The renal clearance of methotrexate is correlated with endogenous creatinine clearance which may provide a guideline to dosage adjustments according to renal function and age. With high dose methotrexate, routine administration of fluid and/or bicarbonate is recommended to prevent intratubular precipitation of the drug.

Biliary excretion of methotrexate constitutes less than 10% of the administered dose. Other extrarenal routes of excretion such as secretion into human breast milk and saliva are negligible.

About a third of an oral dose of methotrexate is metabolised by intestinal bacteria during absorption. The major metabolite is 4-amino-4-deoxy-N10-methylpteroic acid. Small amounts (<11%) of 7 -hydroxymethotrexate have also been found in urine of patients receiving high dose methotrexate therapy. Except for the poly-γ-glutamates, all of the reported metabolites are less effective than methotrexate as an inhibitor of dihydrofolate reductase. As determined by inhibition of DNA synthesis, normal tissues are sensitive to low levels of methotrexate (∼10−8M) Furthermore, toxicity with methotrexate is related to duration of exposure as well as to the dose or plasma concentration.

Impurities, such as methopterin and other byproducts of the synthetic process have been found in commercial parenteral dosage forms of methotrexate. The clinical significance of these impurities requires further study.

For a phase-specific chemotherapeutic agent such as methotrexate, effective plasma levels of the drug should be maintained during the proliferative phase of the tumour cell cycle to achieve a maximum cytotoxic effect. Monitoring the plasma level of methotrexate, particularly during high dose therapy, may provide information regarding impending toxicity and the need for extended citrovorum factor rescue.

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  1. Clinical Pharmacology-Toxicology Center, Departments of Pharmacology and Medicine, University of Kansas Medical Center, Kansas City, Kansas, 66103, USA

    D. D. Shen &  D. L. Azarnoff

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Supported in part by contract No. 1-CM-12184 and grant GM-15956 from the United States Public Health Service.

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Shen, D.D., Azarnoff, D.L. Clinical Pharmacokinetics of Methotrexate. Clin Pharmacokinet 3, 1–13 (1978). https://doi.org/10.2165/00003088-197803010-00001

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