title: An LC/MS/MS method for the quantitation of MTIC (5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), a bioconversion product of temozolomide, in rat and dog plasma.
abstract: A sensitive and selective HPLC/electrospray ionization tandem mass spectrometric (LC/ESI/MS/MS) method for the quantitative determination of MTIC (5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), a pharmacologically active hydrolysis product of temozolomide, was developed and validated over a linear range from 10 to 400 ng ml(-1) in dog plasma and from 10 to 500 ng ml(-1) in rat plasma. This HPLC method utilized small plasma volumes (70 microl), rapid sample processing, and isocratic elusion conditions to achieve sensitive and selective MS/MS detection. Samples were processed and analyzed one at a time every 4.5 min in order to compensate for the inherent instability of MTIC. Both MTIC and the internal standard DTIC [5-(3,3'-N,N'-dimethyltriazen-1-yl)-imidazole-4-carboxamide] were quantitated in the positive ion, selected reaction monitoring (SRM) mode. The lower limit of quantitation (LLOQ) was 10 ng ml(-1) in the plasma from both species. Inter-assay accuracy and precision of all calibration standards and quality control (QC) samples were within +/- 11 and 12%, respectively, with the exception of the LLOQ in rat plasma (17%). The validated method was used to determine the time dependent plasma concentration of MTIC in rats and dogs following a single oral dose of temozolomide. The standard curve and the quality control data indicate that the method performed acceptably throughout the sample analysis period.
authors.affiliation: Drug Metabolism and Pharmacokinetics Department, Schering Plough Research Institute, Kenilworth, NJ 07033, USA. swapan.chowdhury@spcorp.com
authors.forename: S K
authors.initials: SK
authors.lastname: Chowdhury
authors.forename: D
authors.initials: D
authors.lastname: Laudicina
authors.forename: N
authors.initials: N
authors.lastname: Blumenkrantz
authors.forename: M
authors.initials: M
authors.lastname: Wirth
authors.forename: K B
authors.initials: KB
authors.lastname: Alton
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000097:blood*; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000097:blood; D004285:Dogs; D005260:Female; D008297:Male; D013058:Mass Spectrometry; D011786:Quality Control; D051381:Rats; D015203:Reproducibility of Results; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide; D000077204:Temozolomide