Methotrexate Displacement in Man*

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Abstract
Methotrexate (MTX) persists in liver and kidney for several months after administration; in the rat and mouse, the binding site appears to be the enzyme dihydro-folate reductase. If the drug is similarly bound in man, other compounds having an affinity for this enzyme should be able to displace bound MTX. In order to examine this hypothesis, tritium-labeled MTX (2.5 [mu]g/kg; 770 mc/mmole) was administered intravenously to human subjects and, after an interval of 3 weeks, a series of unlabeled compounds tested for ability to displace bound drug. The MTX-displacing ability of the agents tested, administered intravenously, was as follows MTX (unlabeled) > dihydrofolate > folate 5-formyltetrahydrofolate > 5-methyltetrahydrofolate. Since an identical series is obtained if these compounds are listed in order of decreasing in vitro affinity for dihydrofolate reductase, the results are compatible with the hypothesis that, in man, MTX is retained in tissues tightly but reversibly bound to enzyme. Chromatography on DEAE-cellulose revealed that radioactivity in the urine immediately after the initial labeled dose and after the flushing doses consisted of unchanged MTX-H3. In the intervening period, however, considerable amounts of 2 labeled conversion products were excreted; thus the gradual loss of MTX from tissues which occurs in man may result from slow conversion to products with a lower affinity than the parent compound for dihydrofolate reductase.