title: Determination and stability of CP-31398 in plasma from experimental animals by LC-MS/MS.
abstract: A sensitive and accurate approach for the determination of CP-31398 (N-{2-[(E)-2-(4-methoxy-phenyl)-vinyl]-quinazolin-4-yl}-N',N'-dimethyl-propane-1,3-diamine hydrochloride) in rat and dog plasma by LC-MS/MS was validated to support preclinical toxicological and pharmacological studies. Based on the results of stability experiments with diluted CP-31398 solutions using NMR, LC-MS/MS and LC-Q-TOF, all sample preparation and handling steps were performed under yellow light to avoid CP-31398 decomposition. CP-31398 was extracted by protein precipitation with acetonitrile and separated using a Phenomenex Luna 3μm phenyl-hexyl, 100Å, 30×2.0mm column (rat plasma) or a Phenomenex Synergi 4μ Polar-RP, 80Å, 30×2.0mm column (dog plasma) at a flow rate of 0.30mL/min. The mobile phase consisted of A: 1% formic acid in water and B: 1% formic acid in methanol or acetonitrile. Total run times for rat and dog samples were 7 and 8min, respectively, with accompanying retention times of 1.8 for both columns. A turbo ion spray interface was used as the ion source operating in positive mode. Calibration curves were linear from 5 to 1000ng/mL. Linearity was assessed using the external standard method. Within-run and between-run accuracy was 93-109% of the true value for all analytes with precision (SD) of 8% or less for all experiments. The validated method was applied to preclinical toxicology studies in rats and dogs after oral administration of CP-31398.
authors.affiliation: Life Sciences Group, IIT Research Institute, Chicago, IL 60616, USA. mmuzzio@iitri.org
authors.forename: Miguel
authors.initials: M
authors.lastname: Muzzio
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Huang
authors.forename: William D
authors.initials: WD
authors.lastname: Johnson
authors.forename: David L
authors.initials: DL
authors.lastname: McCormick
authors.forename: Izet M
authors.initials: IM
authors.lastname: Kapetanovic
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D018890:Chemoprevention; D002853:Chromatography, Liquid / Q000379:methods; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D008027:Light; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000517:prevention & control; D011743:Pyrimidines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D012015:Reference Standards; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; C402665:CP 31398