Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man.

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 have been studied. Metoprine and etoprine, potent inhibitors of mammalian dihydrofolate reductase, were compared with pyrimethamine, a widely used antimalarial drug. The development of assay procedures in our laboratory and the synthesis of radiolabeled compounds have 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) greater than metoprine (log P = 2.82) greater than pyrimethamine (log P = 2.69). Etoprine has the greatest affinity for plasma proteins, but all three 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 four species. The mean plasma half-lives in man are: pyrimethamine, 85 hr; metoprine, 216 hr; etoprine, 176 hr.