title: Liquid chromatography-tandem mass spectrometric assay for the VEGFR inhibitor cediranib and its primary human metabolite cediranib-N⁺-glucuronide in plasma.
abstract: A quantitative bioanalytical assay for cediranib and its N(+)-glucuronide metabolite was developed and validated. Human plasma samples were pre-treated using protein precipitation with acetonitrile containing erlotinib and CYT-387 as internal standards for the glucuronide metabolite and parent compound, respectively. The extract was diluted with water and injected into the chromatographic system. This system consisted of sub-2 μm particles, a trifunctional bonded octadecyl silica column with gradient elution using 0.005% (v/v) of formic acid in a mixture of water and methanol. The eluate was transferred into the electrospray interface with positive ionization and the analytes were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was validated in a 1-290 ng/ml calibration range for cediranib and 0.2-52 ng/ml for its glucuronide metabolite. The lowest levels of these ranges corresponded to the lower limits of quantification for both compounds. Within day precisions were 4.0-6.7% for cediranib and 4.1-11.9% for its glucuronide, between day precisions were 4.2-10.2 and 4.8-14.4% and accuracies were between 99 and 106 and 84 and 94% for cediranib and its metabolite, respectively. Stabilities of both compounds were sufficient under all relevant conditions. Finally, the assay was successfully used to assess drug levels in a pharmacokinetic mouse study.
authors.affiliation: Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. r.w.sparidans@uu.nl
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: Selvi
authors.initials: S
authors.lastname: Durmus
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry; D002853:Chromatography, Liquid / Q000379:methods*; D020719:Glucuronides / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D016014:Linear Models; D051379:Mice; D011743:Pyrimidines / Q000737:chemistry; D011799:Quinazolines / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*; D007211:Indoles
chemical_list: D001549:Benzamides; D020719:Glucuronides; D011743:Pyrimidines; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; C500926:cediranib; D007211:Indoles