944 Pharmacokinetics of 5,10-methylenetetra-hydrofolate in patients with advanced colorectal cancer

Conversion of 5-fluorouracil to FdUMP and subsequent formation of a ternary complex of FdUMP, thymidylate synthase (TS) and 5,10-methylene-tetrahydrofolate (CH2FH4) results in TS inhibition. CH2FH4 is difficult to use clinically due to instability in contact with oxygen but can be used when reconstituted and injected under oxygen free conditions for which convenient devices are now available. IS patients with advanced colorectal cancer received i.v. push injections of 100 mg (n = 8) or 200 mg (n = 7) CH2FH4, followed 20 minutes later by a rapid injection of 5-FU. Blood samples were collected before and 5, 10, 15, 20, 30, 40, 50 and 60 minutes after CH2FH4 injection. Plasma drug concentrations were analysed by HPLC and area under the curve calculated according to the trapezoidal rule. Peak plasma concentration achieved after 5 min. was 18.6 ± l.3 μmol/l and 43.3 ± 2.6 μmo1/l after 100 and 200 mg CH2FH4 respectively. Mean alfa phase t1/2 was 8.9 ± 0.5 min for the two doses, while mean beta t1/2 was 42 ± 2 min. for the 100 mg dose and 120 ± 3 min for the 200 mg dose. Mean AUC was 263 ± 12 and 1088 ± 37/l mol/l/h after 100 and 200 mg CH2FH4 respectively. Intravenous injection of CH2FH4 increase plasma levels of this active cofactor for TS inhibition and might be an option for increasing therapeutic results of 5-fluorouracil treatment.