title: Quantification of the anti-leukemia drug STI571 (Gleevec) and its metabolite (CGP 74588) in monkey plasma using a semi-automated solid phase extraction procedure and liquid chromatography-tandem mass spectrometry.
abstract: Signal Transduction Inhibitor 571 (STI571, formerly known as CGP 57148B) or Gleevec received fast track approval by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML). STI571 (Gleevec) is a revolutionary and promising new oral therapy for CML, which functions at the molecular level with high specificity. The dramatic improvement in efficacy compared with existing treatments prompted an equally profound increase in the pace of development of Gleevec. The duration from first dose in man to completion of the New Drug Application (NDA) filing was less than 3 years. In addition, recently, FDA approved Gleevec for the treatment of gastrointestinal stromal tumor (GIST). In order to support all toxicokinetic (TK) studies with sufficient speed to meet various target dates, a semi-automated procedure using solid phase extraction (SPE) was developed and validated. A Packard Multi-Probe I and a SPE step in a 96-well plate format were utilized. A 3M Empore octyl (C(8))-standard density 96-well plate was used for plasma sample extraction. A Sciex API 3000 triple quadrupole mass spectrometer with an atmospheric pressure chemical ionization (APCI) interface operated in positive ion mode was used for detection. Lower limits of quantification of 1.00 and 2.00 ng/ml were attained for STI571 and its metabolite, CGP 74588, respectively. The method proved to be rugged and allowed the simultaneous quantification of STI571 and CGP 74588 in monkey plasma. Herein, assay development, validation, and representative concentration-time profiles obtained from TK studies are presented.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA. ray_bakhtiar@merck.com
authors.forename: R
authors.initials: R
authors.lastname: Bakhtiar
authors.forename: L
authors.initials: L
authors.lastname: Khemani
authors.forename: M
authors.initials: M
authors.lastname: Hayes
authors.forename: T
authors.initials: T
authors.lastname: Bedman
authors.forename: F
authors.initials: F
authors.lastname: Tse
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood*; D001549:Benzamides; D002853:Chromatography, Liquid / Q000379:methods*; D000882:Haplorhini; D000068877:Imatinib Mesylate; D013058:Mass Spectrometry / Q000379:methods*; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood*; D015203:Reproducibility of Results
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate