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Tissue-specific Synthesis of Methotrexate Polyglutamates in the Rat¹

Research Institute, Montreal General Hospital, Montreal, Quebec, Canada

² To whom reprint requests should be addressed, at Division of Haematology, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec, Canada.

Purified tritium-labeled methotrexate was administered to rats and Sephadex G-15 gel chromatography was used to study the formation of poly--glutamyl metabolites of methotrexate in different tissues. These metabolites were recognized as tritium-labeled antifolate fractions and were identified by their response to serum pteroylpolyglutamate hydrolases and by cochromatography with authentic standards. After doses equivalent to 15 to 20 mg for man, rat liver and kidney were found to contain both 4-amino-10-methylpteroylglutamyl--glutamic acid and 4-amino-10-methylpteroylglutamyl--glutamyl--glutamic acid. With one-third of the dose, only 4-amino-10-methylpteroylglutamyl--glutamic acid was found. Synthesis of methotrexate polyglutamates in liver and kidney was limited to the interval immediately following methotrexate administration and appeared to occur by sequential addition of single glutamyl residues to so-called "free" intracellular methotrexate. No synthesis of methotrexate polyglutamates was demonstrated in small intestine or thymus. After formation, 4-amino-10-methylpteroyglutamyl--glutamic acid disappeared from liver and kidney with a half-time of 6.5 days. The effect of these metabolites of methotrexate on cell metabolism is unknown.

¹ This work was supported by Grant MA-2384 from the Medical Research Council of Canada and by a grant from the Cancer Research Society, Inc.

Received 5/31/74. Accepted 7/16/75.

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