title: Characterisation of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity.
abstract: The experimental antineoplastic agent temozolomide was not metabolised in vitro at a measurable rate by mouse liver fractions. In contrast, the temozolomide analogue 3-methylbenzotriazinone was metabolically N-demethylated by hepatic microsomes to yield benzotriazinone. The major route of excretion of [14C]-labelled temozolomide in mice was via the kidneys. An acidic metabolite of temozolomide, probably a conjugate, was found in the urine of mice, but its identity could not be established unambiguously. Spectroscopic analysis and chemical tests revealed that it possesses an intact NNN-linkage. Another metabolite was found in the urine of patients but not of mice. This metabolite was identified as the 8-carboxylic acid derivative of temozolomide. Unlike the unknown species, this metabolite was cytotoxic against TLX5 lymphoma cells in vitro.
authors.affiliation: Cancer Research Campaign Experimental Chemotherapy Group, Pharmaceutical Sciences Institute, Aston University, Birmingham, England, U.K.
authors.forename: L L
authors.initials: LL
authors.lastname: Tsang
authors.forename: P B
authors.initials: PB
authors.lastname: Farmer
authors.forename: A
authors.initials: A
authors.lastname: Gescher
authors.forename: J A
authors.initials: JA
authors.lastname: Slack
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity / Q000652:urine*; D002851:Chromatography, High Pressure Liquid; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000633:toxicity / Q000652:urine; D004341:Drug Evaluation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D008223:Lymphoma / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008862:Microsomes, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D000077204:Temozolomide; D013953:Thymus Neoplasms / Q000188:drug therapy; D014227:Triazines / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D014227:Triazines; C066243:3-methylbenzotriazin-4-one; D003606:Dacarbazine; D000077204:Temozolomide