Polyglutamation of the antifolate anticancer drug N10-propargyl-5,8-dideazafolic acid (CB 3717) in the mouse.

The antifolate drug N10-propargyl-5,8-dideazafolic acid was shown to be metabolized to its gamma-glutamyl conjugates in mouse liver and kidneys after administration at a dose of 20 mg/kg. The tissue levels of both CB 3717 and its polyglutamates were time dependent. However, in liver the clearance of polyglutamated conjugates was 10 times slower than that of the parent compound. In liver after 48 hr up to 50% of recovered radioactivity consisted of CB 3717 polyglutamates. In addition to polyglutamate derivatives, in both liver and kidney, 72 hr after CB 3717 administration another minor CB 3717 metabolite(s), unsusceptible to conjugase treatment, was detected. The nature of this metabolite(s) is currently unknown.