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

• Published in: Drug metabolism and disposition Vol. 6; no. 3; p. 329
• Main Authors: Cavallito, J C, Nichol, C A, Brenckman, Jr, W D, Deangelis, R L, Stickney, D R, Simmons, W S, Sigel, C W
• Format: Journal Article
• Language: English
• Published: United States 01-05-1978
• Subjects: Adult; Animals; Chemical Phenomena; Chemistry, Physical; Dogs; Folic Acid Antagonists; Half-Life; Humans; Kinetics; Male; Protein Binding; Pyrimethamine - analogs & derivatives; Pyrimethamine - metabolism; Rats; Tissue Distribution
• ISSN: 0090-9556

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.