title: Simultaneous determination of Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone (SU5416) and its interconvertible geometric isomer (SU5886) in rat plasma by LC/MS/MS.
abstract: Z-3-[(2,4-Dimethylpyrrol-5-yl)methylidenyl]-2-indolinone (SU5416) is a cytostatic substance in development as an anti-angiogenic agent. SU5416 exists as the thermodynamically stable cis or Z-isomer as a solid. Studies have shown that in light exposed solutions of SU5416, the unstable trans or E-isomer, namely SU5886, is formed. The E-isomer converts back to the Z-isomer when protected from light. The E-isomer is unstable for synthesis and isolation; therefore, the analytical standard of the E-isomer is not available. In this study, a simple, fast and reliable LC/MS/MS method has been developed to determinate both isomers simultaneously in rat plasma samples to support the study of disposition kinetics of SU5416. This method is sensitive (limit of quantitation (LOQ=0.5 ng/mL)), reproducible and has a wide linear range (0.5-2500 ng/mL). There was no conversion between E- and Z-isomer during sample preparation procedure and sample determination with LC/MS/MS. Experimental results proved that SU5416 and SU5886 have identical detection response. Therefore, SU5416 (Z-isomer) was used successfully as analytical standard for SU5886 (E-isomer). This method has been applied to rat plasma samples obtained from a pharmacokinetic study. This study underscores the use of LC/MS/MS technique for bioanalytical methods where analytical standards are not available and analytes are interconvertible.
authors.affiliation: Department of Bioanalysis and Phamarcokinetcs, Sugen, 230 E. Grand Ave., South San Francisco, CA 98080, USA. yzhao@exelixis.com
authors.forename: Yeping
authors.initials: Y
authors.lastname: Zhao
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
mesh_terms: D020533:Angiogenesis Inhibitors / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D015507:Drugs, Investigational / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007211:Indoles / Q000097:blood* / Q000493:pharmacokinetics / Q000592:standards; D013058:Mass Spectrometry / Q000379:methods*; D011758:Pyrroles / Q000097:blood* / Q000493:pharmacokinetics / Q000592:standards; D051381:Rats; D012015:Reference Standards; D015203:Reproducibility of Results; D013237:Stereoisomerism
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D015507:Drugs, Investigational; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib