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The Metabolic Fate of Tritiated Methotrexate

I. Absorption, Excretion, and Distribution in Mice, Rats, Dogs and Monkeys

( Laboratory of Chemical Pharmacology, National Cancer Institute, N1H, Bethesda, Maryland)

The absorption, excretion, distribution, metabolism, and serum protein binding of tritium-labeled methotrexate (MTX)¹ has been studied in a variety of laboratory mammals. In all species studied the drug is excreted entirely in urine and stool, and largely within the 24 hr following administration. MTX is incompletely absorbed from the gastrointestinal tract. It is stored chiefly in the liver, to a degree which is in part dependent on dose. However, prolonged treatment with MTX does not measurably increase either the levels of retained drug or levels of the enzyme dihydrofolate reductase (DHFR) to which it is bound.

There is no definite in vivo evidence of metabolism of MTX by any of the animal species studied. The 9000 x g fraction of rat liver homogenates, capable of oxidizing dichloromethotrexate (DCM) in vitro, failed to metabolize MTX.

MTX is bound to serum proteins in all species studied. In each case the degree of binding is similar over a wide range of concentrations and approximates 50% in the mouse, 66% in the rat, and 40% in the dog.

MTX is consistently more toxic per unit weight than its chlorinated derivative, DCM, and at the same time is remarkably less effective in the therapy of L1210 murine leukemia. Possible reasons for these discrepancies are discussed.

¹ The abbreviations used are: MTX, methotrexate; MTX-³H, tritiated methotrexate; DHFR, dihydrofolate reductase; DCM, dichloromethotrexate; PGA, pteroylglutamic acid; DEAE, diethylaminoethyl; EDTA, ethylenediamine tetraacetate; AMT, aminopterin.

Received 12/17/64. Revised 3/31/65.