5-methyltetrahydrofolate and Lymphoma

DL-N5-Methyltetrahydrohomofolate (MTHHF; NSC-139490; N- [(4-[(2-(2-amino-3,4,5,6,7,8-hexahydro-4-oxo-5-methyl-6- pteridinyl)ethyl) amino) benzoyl)] -L-glutamate), a new folate antagonist of relatively low toxicity, is active against experimental tumor systems resistant to methotrexate and consequently now in clinical trial. We investigated its clinical pharmacokinetics in six patients; four of them received by rapid i.v. infusion tracer doses of [N5-methyl-14C]MTHHF ranging from 13 to 16 mg/sq m, and 2 received 150 mg/sq m; the total radioactivity dose was 100 to 200 mu Ci/patient. MTHHF was assayed by radiochemical and chromatographic techniques. The elimination of MTHHF from the plasma followed a triexponential pattern, with a harmonic mean initial half-life of 20.1 min, an intermediary half-life of 4.5 hr, and a terminal half-life of 74.6 hr. The apparent volume of distribution was 1.6 liters/kg, suggesting rapid and extensive tissue binding. This, together with the low total clearance of 0.2 ml/kg/min, contributed to the long half-life of this agent. Although 68% of the administered dose was excreted in the urine on the first day, only an additional 1% was excreted on the ensuing 3 days. In the two patients who received the higher dose, very little MTHHF was found in the cerebrospinal fluid. In concentrations ranging from 25 to 500 micrograms/ml, the drug was about 50% bound to plasma protein. MTHHF was not metabolized in humans as also reported in animals. These results suggest that MTHHF is excreted in the bile to certain extent. Moreover, since it tends to localize and persist in the body, to forestall cumulative toxicity, frequent administration of this agent should be undertaken only with caution.

Topics: Breast Neoplasms; Carbon Radioisotopes; Female; Hodgkin Disease; Humans; Kinetics; Lymphoma; Tetrahydrofolates

The liquid-chromatographic measurement of 5-methyltetrahydrofolate in biological fluids is described. The sensitivity of the spectrophotofluorometric detector used allows direct evaluation of basal concentrations of the compound in plasma. Because it is resolved from the other common folates and from methotrexate, the procedure is suitable for monitoring it in plasma of patients receiving high-dose therapy with methotrexate.

Topics: Adult; Animals; Chromatography, High Pressure Liquid; Dogs; Folic Acid; Humans; Leucovorin; Leukemia, Lymphoid; Lymphoma; Male; Middle Aged; Spectrophotometry, Ultraviolet; Tetrahydrofolates; Time Factors