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Distribution Studies of Tetrahydrohomofolic Acid (NSC 89473) in Mice¹

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

Tetrahydrohomofolic acid, like tetrahydrofolic acid, was found to be unstable in acid pH, liberating free diazotizable amine which could be estimated by the Bratton-Marshall reagent. An assay procedure based on this observation has been developed to determine the drug levels in biological material, and the tissue distribution of the drug in normal mice has been determined. At the optimum therapeutic dose level (400 mg/kg i.p.), the peak levels of the drug in blood plasma, kidney, lung, spleen, and brain occurred at 30 min or less and in liver at 60 min or less after injection, and declined rapidly thereafter. The peak drug level in kidney was 798 µg/g. Plasma, liver, lung, spleen, and brain contained 59, 42, 40, 22, and 4% of the kidney drug levels, respectively. At a higher dose level (800 mg/kg i.p.), plasma, lung, and brain attained peak levels in 30 min, spleen and liver in 1 hr, and kidney in 2 hr. The peak drug levels in plasma, liver, lung, spleen, and brain were 82, 36, 47, 28, and 8% of the peak kidney drug level, respectively. In kidney and lung, the half-life of the drug was prolonged considerably at the higher dose level. At the lower dose level, the values in kidney and lung were 120 and 96 min, but at the higher dose level, the values increased to 426 and 192 min, respectively. The peak drug level attained in plasma after s.c. administration was 25% of that attained after i.p. administration, and hardly any drug was detected in plasma after p.o. administration. The drug levels in erythrocytes in vivo as well as in vitro were 1.8 times higher than the drug levels in plasma. After a dose of 400 mg/kg i.p., 26% was recovered in the urine over a 9-day period, 21% of which was excreted within 4 hr.

¹ This work was partially supported by Contract PH-43-68-1283 from Chemotherapy, National Cancer Institute, NIH.

Received 1/20/69. Accepted 7/31/69.