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The Influence of Folate Antagonists on the Metabolism of Folic Acid and Its Reduced Derivatives in Rat Liver and Kidney¹

The University of Rochester School of Medicine, Oncology Division, The Genesee Hospital, Rochester, New York 14607

Uptake and conversion of [³H]folic acid to polyglutamate derivatives by rat liver and kidney were inhibited by methotrexate or aminopterin (15 mg/kg body weight) and DL-tetrahydromethotrexate (30 mg/kg body weight). In contrast, these antagonists did not influence the conversion of L-5-formyl-[³H]tetrahydrofolic acid or L-5-methyl[³H]tetrahydrofolic acid to polyglutamate derivatives and had little effect on the uptake of reduced folate derivatives.

When [³H]methotrexate, [³H]aminopterin, and DL-[³H]tetrahydromethotrexate were administered in small amounts (15 µg/kg body weight), no metabolites of these compounds were observed. However, at higher doses of [³H]methotrexate (300 µg/kg body weight), more than 30% of the radioactivity remaining in the tissue 24 hr after administration could be attributed to a metabolite of methotrexate. This metabolite was tentatively identified as methotrexate diglutamate.

¹ This research was supported by USPHS Grant CA-16269 from the National Cancer Institute and by a grant from the Monroe County Cancer and Leukemia Association.

Received 3/29/76. Accepted 10/18/76.