Development of a format for abstracting dose-response information from published studies for use in quantitative structure-activity relationships (QSARs).

The Toxic Substances Control Act subjects some 70 000 chemicals to regulatory action. However, empirical testing of the biological activities of this number of compounds is not feasible. An attractive alternative is the development of predictive methodology which can be used to estimate the potency of an untested compound toward a specific biological receptor. Prerequisite to such an enterprise is the highly systematic compilation of dose-response information for a wide range of biological end points and for a wide variety of molecular species. A format is described for abstracting relevant information from published studies. The format outlines the test system, experimental conditions, response analysis, exposure protocol, and results and presents the original data, all in an organized form. Regression analysis is used to estimate thresholds and potencies in the various test systems. The data may then be used to develop a predictive methodology.

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.

Quantitative thin-layer chromatography of pyrimethamine and related diaminopyrimidines in body fluids and tissues.

Several 2,4-diaminopyrimidines which inhibit the enzyme dihydrofolate reductase are quantitated following extraction and separation on silica gel thin-layer chromatographic plates. These compounds are candidates for the treatment of brain tumors and meningeal leukemia, because they have the ability to cross the blood-brain barrier. The ultraviolet absorption of the pyrimidine ring at 275 nm is utilized to quantitate these compounds on thin-layer chromatographic plates with a scanning instrument. This method offers the advantages of speed, specificity, versatility and sensitivity, and has proven to be satisfactory for the measurement of as little as 10 ng/ml of these compounds in biological fluids.