title: Quantitation of unbound sunitinib and its metabolite N-desethyl sunitinib (SU12662) in human plasma by equilibrium dialysis and liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study.
abstract: A rapid, selective, and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of unbound sunitinib and its active metabolite N-desethyl sunitinib in plasma. Plasma and post-dialysis buffer samples were extracted using a liquid-liquid extraction procedure with acetonitrile-n-butylchloride (1:4, v/v). Chromatographic separation was achieved on a Waters X-Terra® MS RP(18) column with a mobile phase consisting of acetonitrile and water (60:40, v/v) containing formic acid (0.1%, v/v) using an isocratic run, at a flow-rate of 0.2 mL/min. Analytes were detected by electrospray tandem mass spectrometry in the selective reaction monitoring mode. Linear calibration curves were generated over the ranges 0.1-100 and 0.02-5 ng/mL for sunitinib and 0.2-200 and 0.04-10 ng/mL for N-desethyl sunitinib in plasma and in phosphate-buffered solution, respectively. The values for both within-day and between-day precision and accuracy were well within the generally accepted criteria for analytical methods. The analytical range was sufficient to determine the unbound and total concentrations of both analytes. The method was applied for measurement unbound concentrations in addition to total concentrations of sunitinib and its metabolite in plasma of a cancer patient receiving 50 mg daily dose.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Linping
authors.initials: L
authors.lastname: Xu
authors.forename: John F
authors.initials: JF
authors.lastname: Deeken
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002853:Chromatography, Liquid / Q000379:methods*; D017321:Clinical Trials, Phase I as Topic; D004355:Drug Stability; D006801:Humans; D007211:Indoles / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D011758:Pyrroles / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000077210:Sunitinib; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C544393:SU 12662; D000077210:Sunitinib