PT  - JOURNAL ARTICLE
AU  - J C Cavallito
AU  - C A Nichol
AU  - W D Brenckman, Jr
AU  - R L Deangelis
AU  - D R Stickney
AU  - W S Simmons
AU  - C W Sigel
TI  - 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.
DP  - 1978 May 01
TA  - Drug Metabolism and Disposition
PG  - 329--337
VI  - 6
IP  - 3
4099  - http://dmd.aspetjournals.org/content/6/3/329.short
4100  - http://dmd.aspetjournals.org/content/6/3/329.full
SO  - Drug Metab Dispos1978 May 01; 6
AB  - 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.