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The Pharmacological Basis for the Prolonged Antimalarial Activity of Pyrimethamine¹

After oral administration to human subjects, pyrimethamine could be detected chemically and microbiologically for seven days in the serum and for eleven days in the urine. Urinary excretion during the first five days accounted for about twelve per cent of the dose administered. The excretion patterns of materials measured by chemical and microbiological procedures were similar, an observation which speaks against conversion of the parent drug to a metabolite possessing greater anti-folic acid activity.

When administered orally to monkeys, pyrimethamine could be detected for at least five days in the serum and seven days in the urine. Urinary recovery in this period ranged from twenty to forty per cent by chemical determination and from ten to thirty per cent by microbiological assay. Chemically determinable pyrimethamine in both serum and urine was always greater than that measured microbiologically indicating that in the monkey pyrimethamine is converted to a metabolite which has less anti-folic activity than the parent compound.

The "anti-folic acid" activity in urine of human subjects and monkeys receiving pyrimethamine behaved chemically like the parent drug. Evidence for the presence of non-basic pyrimethamine metabolite(s) possessing a higher order of anti-folic activity than the parent compound was not obtained.

Correlation of these findings with earlier observations on the antimalarial activity of pyrimethamine suggests that the prolonged suppressive activity of this compound against infections with Plasmodium vivax in man and P. cynomolgi in the rhesus monkey is due to retention of the parent compound.

¹ This study was supported in part by a research grant E824 from the National Microbiological Institute, National Institutes of Health, U. S. Public Health Service.

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