title: In vivo and in vitro metabolism of 5-deazaacyclotetrahydrofolate, an acyclic tetrahydrofolate analogue.
abstract: 5-Deazaacyclotetrahydrofolate is a cytotoxic tetrahydrofolate analogue which inhibits glycinamide ribonucleotide transformylase (Kelley et al., J. Med. Chem., 33: 561-567, 1990). Cultured mouse L-cells and human MCF-7 and MOLT-4 cells concentrated the drug several hundred-fold after 24 h of continuous exposure to a cytotoxic level (100-200 nM) of radiolabeled drug. High performance liquid chromatography analysis revealed that each cell type metabolized greater than or equal to 80% of the internalized drug to polyglutamated forms, which are more potent glycinamide ribonucleotide transformylase inhibitors. In L-cells, 45% of the polyglutamated metabolites were also N-formylated. The pharmacokinetics and distribution of [14C]-deazaacyclotetrahydrofolate were studied in C57BL/6 male mice. Its plasma half-life was 2.15 h. Radiolabel was concentrated to well above plasma level in the kidney, pancreas, and liver. Metabolism was examined in tumor-bearing and in normal mice. Twenty-four h after a single i.p. injection (50 mg/kg), drug equivalents were 0.6 nmol/g (83% polyglutamated) in colon-38 adenocarcinoma carried s.c., 2.4 nmol/g (100% polyglutamated) in ascitic P388 cells, and 3.7 nmol/g (76% polyglutamated and approximately 20% formylated) in mouse liver. Elimination was mostly in the urine as unmetabolized drug. Feces contained 5-deazaacyclotetrahydropteroate (parent compound less glutamate). In conclusion, 5-deazaacyclotetrahydrofolate was shown to be concentrated to well above the extracellular level and metabolized to more active polyglutamated forms by transformed cells grown in culture and in mice.
authors.affiliation: Department of Molecular Genetics and Microbiology, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
authors.forename: M H
authors.initials: MH
authors.lastname: Hanlon
authors.forename: R
authors.initials: R
authors.lastname: Ferone
authors.forename: R J
authors.initials: RJ
authors.lastname: Mullin
authors.forename: B R
authors.initials: BR
authors.lastname: Keith
mesh_terms: D000818:Animals; D001682:Biological Availability; D001943:Breast Neoplasms / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003240:Connective Tissue Diseases / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D013763:Tetrahydrofolates / Q000378:metabolism* / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D005971:Glutamates; D013763:Tetrahydrofolates; C060147:5-deaza-5,6,7,8-tetrahydrofolic acid