Pharmacokinetics of methotrexate

Abstract

Methotrexate (Mtx) is a competitive inhibitor of the enzymatic activity of dihydrofolate reductase, decreasing the reduction of folic acid to tetrahydrofolate and thereby the activity of thymi dilate kinase. The net effect is a decrease in biosynthesis of deoxyribonucleic acid (DNA) primarily, but also of ribonucleic acid (RNA) and protein. Whereas the plasma elimination halflife of Mtx has previously been reported as 2 to 10 hours, we have recently demonstrated that intravenous administration of 30 mg 3H‐Mtx/M2 to patients with a variety of malignancies is followed by a triphasic disappearance of the drug from plasma with a half‐life of 0.75 ± 0.11, 3.49 ± 0.55, and 26.99 ± 0.44 hr, respectively. 1 Similar values were obtained when the rate of excretion of MTx in urine was determined. The clearance in urine was 78 ml/min, and Mtx appeared to be reabsorbed at very low plasma concentrations. It was also noted that ingestion of meals, but not changes in pH, were associated with an increased rate of excretion, suggesting an enterohepatic circulation.