title: Development and validation of a liquid chromatography/tandem mass spectrometry method for the determination of the novel anticancer agent 17-DMAG in human plasma.
abstract: An accurate, sensitive, robust and selective liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the determination of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin hydrochloride (17-DMAG) in human plasma has been developed and validated. Plasma samples were prepared by liquid/liquid extraction with ethyl acetate. The chromatographic separation was achieved within 9 min on a Synergy Polar column with a linear gradient and a mobile phase consisting of methanol and 0.1% formic acid in water. Detection of 17-DMAG and the internal standard (IS), olomoucine, was achieved by MS/MS with electrospray ionisation in positive ion mode. The calibration curve, ranging from 1.89 to 1890 nM, was linear r > 0.994 using a 1/y2 weighted linear regression. The assay showed no significant interferences from endogenous compounds. The lower limit of quantitation (LLOQ) was 1.89 nM, using 250 microL of plasma, with inter-assay precision (%RSD) and accuracy (%RE) values of 11.6% and -5.8%, respectively. Intra-assay precision ranged from 7.8-13.6%. The method described here is being used to evaluate the pharmacokinetic profiles of 17-DMAG given as a once weekly infusion in patients with advanced solid tumours.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratory, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Moreno-Farre
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Asad
authors.forename: Simon
authors.initials: S
authors.lastname: Pacey
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D016227:Benzoquinones / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D007701:Kinetin / Q000097:blood; D047029:Lactams, Macrocyclic / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C090046:olomoucine; D007701:Kinetin