title: Quantitative determination of the novel anticancer drug E7070 (indisulam) and its metabolite (1,4-benzenedisulphonamide) in human plasma, urine and faeces by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry.
abstract: E7070 (indisulam) is a novel anticancer drug currently undergoing clinical investigation. We present a sensitive and specific method for the quantitative determination of E7070 and its metabolite M1 (1,4-benzenedisulphonamide) in human plasma, urine and faeces. The analytes and their tetra-deuterated analogues, which were used as internal standards, were isolated from the biological matrix by solid-phase extraction with OASIS cartridges (0.5 mL plasma or 1 mL urine) and by liquid-liquid extraction with ethyl acetate at pH 5 (1 mL faecal homogenate). The analytes were separated on a C8 reversed-phase chromatographic column and analyzed using electrospray ionization and tandem mass spectrometric detection in the negative ion mode. The validated concentration ranges in plasma were 0.1-20 microg/mL for E7070 and 0.01-2 microg/mL for M1. In urine and faecal homogenate, a concentration range from 0.05-10 microg/mL or microg/g, respectively, was validated for both analytes. Validation of the plasma assay was performed according to the most recent FDA guidelines. The assay fulfilled all generally accepted requirements for linearity (r > 0.99, residuals between -8 and 10%), accuracy (-13.5 to 1.4%) and precision (all less than 11%) in the tested matrices. We investigated recovery, stability (working solutions at -20 degrees C and at room temperature, biological matrices at -20 degrees C, room temperature and after 3 freeze/thaw cycles; final extracts at room temperature) and robustness. All these parameters were found acceptable. This method is suited for mass balance studies or therapeutic drug monitoring, as demonstrated by a case example showing plasma concentrations and cumulative excretion of E7070 and M1 in urine and faeces. Furthermore, we show the presence of E7070 metabolites in patient urine.
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. APJBE@SLZ.NL
authors.forename: Jan Hendrik
authors.initials: JH
authors.lastname: Beumer
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.forename: Michel J X
authors.initials: MJ
authors.lastname: Hillebrand
authors.forename: Lianda G A H
authors.initials: LG
authors.lastname: Nan-Offeringa
authors.forename: Karen
authors.initials: K
authors.lastname: Foley
authors.forename: S Murray
authors.initials: SM
authors.lastname: Yule
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000970:Antineoplastic Agents / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005243:Feces / Q000737:chemistry; D006801:Humans; D007275:Injections, Intravenous; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013449:Sulfonamides / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides