title: Simultaneous determination and validation of oncrasin-266 and its metabolites by HPLC-MS/MS: Application to a pharmacokinetic study.
abstract: Oncrasins are a class of RNA polymerase II inhibitors. Oncrasin-72 is an indole-3 carbinol analog that has shown to inhibit growth and induce the cell death of various human cancer cell lines. Oncrasin-266, a prodrug of oncrasin-72, has been shown to have improved pharmacokinetic properties and safety than Oncrasin-72. With respect to the potential therapeutic advantages of this class of compounds, there is a need for further preclinical assessment for future clinical trials. The development of and validation of an analytical method is essential for the quantification of oncrasins in biological fluids for pharmacokinetic studies. This study focuses on the HPLC-MS/MS method development and validation of oncrasin-266, oncrasin-72 and its aldehyde metabolite in rat plasma. Blank rat plasma, coupled with 1-(3-chlorobenzyl)-1H-indole, as internal standard, was used for generating standard curves ranging from 1 to 250ng/mL for oncrasin-266 and oncrasin-72; and 0.5-125ng/mL for the aldehyde metabolite. The chromatographic separation was achieved by a Zorbax 300SB-C18 HPLC column at 50°C with a flow rate of 1.1mL/min under gradient elution. Mass detection was performed under positive ionization electrospray. Intra- and inter-day accuracy and precision of the assay were less than 10%. We report a simple, specific and reproducible HPLC-MS/MS method for the quantification of oncrasins in rat plasma. This study was successfully used for the quantification of oncrasins in rat plasma for pharmacokinetic studies in three dose groups of 10, 25, and 50mg/kg via intravenous administration.
authors.affiliation: Department of Pharmaceutical and Environmental Health Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: White
authors.affiliation: Department of Thoratic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical and Environmental Health Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Thoratic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
authors.affiliation: Department of Pharmaceutical and Environmental Health Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA. Electronic address: liang_dx@tsu.edu.
authors.forename: Dong
authors.initials: D
authors.lastname: Liang
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004355:Drug Stability; D007211:Indoles / Q000097:blood* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D016014:Linear Models; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D007211:Indoles; C000596412:oncrasin-266
keywords: LC–MS/MS; Metabolite; Oncrasin; Pharmacokinetics; Prodrug