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Reduction and Metabolism of Dihydrohomofolate in Rhesus Monkeys¹

Microbiological Associates [L. C. M., A. S. P.] and National Cancer Institute [J. A. R. M.], NIH, Bethesda, Maryland 20014

The purpose of this study was to determine whether monkeys could generate tetrahydrohomofolate from dihydrohomofolate since, in monkeys as in humans, dihydrofolate reductase has very low specific activity. Dihydrohomofolate, 3',5'-tritium labeled, was given i.v. to two male rhesus monkeys. One was sacrificed after 30 min, and the organ extracts were analyzed by diethylaminoethyl cellulose column chromatography, UV-absorption spectroscopy, and radioactivity assays. Blood and urine were collected from the other monkey for a 24-hr period. Radioactivity levels in plasma and packed blood cells decreased rapidly to 90% of the peak levels within 70 min. An additional 7.5 to 9.5% of the radioactivity disappeared during the next 24-hr period. Drug levels in lung, heart, spleen, intestine, liver, and kidney at 30 min after administration were, respectively, 0.78, 0.56, 0.37, 1.5, 2.2, and 12.1 times that in plasma. This indicated higher uptake of the drug by the intestine, liver, and kidney relative to other tissues.

Column chromatography of tissues, plasma, and urine indicated that plasma contained large amounts of dihydrohomofolate, trace amounts of tetrahydrohomofolate, and several metabolites that were detectable only on the radiochromatogram and not by ultraviolet light absorption. Packed red blood cells did not contain either of these two reduced homofolates, but contained several detectable transformation products on the radiochromatogram, none of which could be identified as p-aminobenzoyl-l-glutamic acid, a major decomposition product of the drug. In the liver, only tetrahydrohomofolate was found, suggesting that monkey liver has the capability to generate tetrahydrohomofolate from dihydrohomofolate. Urinary excretion of the radioactivity was only 29% of the dose during the 24-hr period, which might be due in part to possible binding of the drug with plasma proteins and tissues and in part to excretion via other routes.

¹ This work was supported in part by Contract NO1-CM-33728 with Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health, Education and Welfare, Bethesda, Md. 20014.

² To whom reprint requests should be addressed at Cancer Chemotherapy Department, Microbiological Associates, 5221 River Road, Bethesda, Md. 20016.

Received 12/ 4/73. Accepted 8/ 7/74.