title: High-performance liquid chromatographic analysis of the investigational anticancer drug 9-aminocamptothecin, as the lactone form and as the total of the lactone and the hydroxycarboxylate forms, in micro-volumes of human plasma.
abstract: A high performance liquid chromatographic (HPLC) assay is described for the determination of the investigational anticancer drug 9 aminocamptothecin (9-AC) as the lactone form (9AC(lac)) and as the total of the lactone and hydroxycarboxylate forms (9AC-(tot)), in micro volumes of plasma. The analytical methodology reported here involves a protein precipitation step with cold methanol (-30 degrees C) as sample pretreatment procedure. The methanolic extract is used for the determination of 9AC-(tot). The intact (active) lactone form of 9-AC is separated from the hydroxycarboxylate form in the methanolic plasma extract by solid phase extraction within 48 h after sampling and deproteination. After evaporation to dryness (nitrogen, 40 degrees C) the extract can be stored at -70 degrees C for at least 3 weeks. The drug is analysed by reversed-phase liquid chromatography on a Zorbax SB RP-18 column, using methanol-water eluent (pH 2.2) and fluorescence detection. The presented assay is linear over a concentration range 0.2-100 ng.ml-1 with a detection limit and a limit of quantitation of 0.05 and 0.2 ng.ml-1, respectively, for both 9-AC(tot) and 9-AC(lac) using a 100 ml plasma sample. The proposed method has been implemented in a phase I clinical trial for pharmacokinetic evaluation of this potential new drug.
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Gijn
authors.forename: V M
authors.initials: VM
authors.lastname: Herben
authors.forename: M J
authors.initials: MJ
authors.lastname: Hillebrand
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: A
authors.initials: A
authors.lastname: Bult
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy; D004355:Drug Stability; D006801:Humans; D007783:Lactones / Q000032:analysis / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; C080125:9-aminocamptothecin; D002166:Camptothecin