LIPID-SOLUBLE INHIBITORS OF DIHYDROFOLATE-REDUCTASE .1. KINETICS, TISSUE DISTRIBUTION, AND EXTENT OF METABOLISM OF PYRIMETHAMINE, METOPRINE, AND ETOPRINE IN RAT, DOG, AND MAN

  • 1 January 1978
    • journal article
    • research article
    • Vol. 6  (3) , 329-337
Abstract
With the aim of developing anticancer compounds which overcome some of the clinical limitations of the polar dihydrofolate reductase inhibitor, methotrexate, the physicochemical properties, kinetics and metabolism of a series of lipid-soluble 2,4-diamino-5-phenylpyrimidine folate antagonists were studied. Metoprine and etoprine, potent inhibitors of mammalian dihydrofolate reductase, were compared with pyrimethamine, a widely used antimalarial drug. The development of assay procedures and the synthesis of radiolabeled compounds enabled a comparison of the kinetic characteristics and tissue distribution of these compounds in several species. The relative lipophilicities as indicated by the octanol/water partition coefficient are: etoprine (log P = 3.19) > metoprine (log P = 2.82) > pyrimethamine (log P = 2.69). Etoprine has the greatest affinity for plasma proteins, but all 3 compounds are bound to human plasma protein by 87% or more at therapeutic concentrations. Pharmacokinetic studies in the mouse, rat, dog and man indicate that metoprine has the longest plasma half-life in all 4 species. The mean plasma half-lives in man are: pyrimethamine, 85 h, metoprine, 216 h and etoprine, 176 h.