Clinical Pharmacokinetics of 5-Methyltetrahydrohomofolate

Ti Li Loo, Liu Jiushi, Katherine Lu, Niramol Savaraj

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 μCi/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 μg/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.

Original languageEnglish (US)
Pages (from-to)921-924
Number of pages4
JournalCancer Research
Issue number2
StatePublished - Feb 1 1983
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Clinical Pharmacokinetics of 5-Methyltetrahydrohomofolate'. Together they form a unique fingerprint.

Cite this