title: Analytical procedure for the determination of the new antitumour drug N-benzoylstaurosporine and three potential metabolites in human plasma by reversed-phase high-performance liquid chromatography.
abstract: The staurosporine derivative, N-benzoylstaurosporine (CGP 41 251; I), is a protein kinase C inhibitor that has been selected for phase I clinical evaluation in cancer patients. We have developed a selective and sensitive assay of the drug and three potential metabolites in human plasma. The method is based on reversed-phase high-performance liquid chromatography with fluorescence detection. The sample pretreatment involves liquid-liquid extraction with diisopropyl ether with recoveries over 88%. The limit of detection and limit of quantitation of the parent compound and two metabolites were 0.5 and 1.0 ng/ml, respectively. For the third metabolite the limit of detection and limit of quantitation were 1.0 and 2.0 ng/ml, respectively. Linear calibration lines were obtained over the range of 1-1000 ng/ml. The between-day and within-day precisions were < 7.1% for all the analytes. In plasma the compounds were stable for at least one month if stored at -30 degrees C or below. The applicability of the method for in vivo studies has been demonstrated in a pharmacokinetic study in rat receiving 0.5 mg/kg of the drug as an intravenous bolus injection. Compound I and two metabolites were detected.
authors.affiliation: Slotervaart Hospital, Amsterdam, Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Gijn
authors.forename: O
authors.initials: O
authors.lastname: van Tellingen
authors.forename: J J
authors.initials: JJ
authors.lastname: de Clippeleir
authors.forename: M J
authors.initials: MJ
authors.lastname: Hillebrand
authors.forename: E
authors.initials: E
authors.lastname: Boven
authors.forename: J B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: S
authors.initials: S
authors.lastname: Schwertz
authors.forename: P
authors.initials: P
authors.lastname: Graf
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000470:Alkaloids / Q000097:blood* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004355:Drug Stability; D004987:Ethers; D005615:Freezing; D006801:Humans; D008297:Male; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D012680:Sensitivity and Specificity; D019311:Staurosporine / Q000031:analogs & derivatives*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D004987:Ethers; C011779:diisopropyl ether; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin