title: Simultaneous determination of the lactone and carboxylate forms of irinotecan (CPT-11) and its active metabolite SN-38 by high-performance liquid chromatography: application to plasma pharmacokinetic studies in the rat.
abstract: Irinotecan (CPT-11) and its main metabolite SN-38 are potent anticancer derivatives of camptothecin (CPT), with active lactone and inactive carboxylate forms coexisting. A simple and sensitive HPLC method using the ion-pairing reagent tetrabutylammonium hydrogen sulfate (TBAHS) was developed to simultaneously determine all four analytes in rat plasma samples. Camptothecin (CPT) was used as internal standard. The mobile phase was 0.1M potassium dihydrogen phosphate containing 0.01 M TBAHS (pH 6.4)-acetonitrile (75:25, v/v). Separation of the compounds was carried out on a Hypersil C18 column, monitored at 540 nm (excitation wavelength at 380 nm). All four compounds gave linear response as a function of concentration over 0.01-10 microM. The limit of quantitation in rat plasma was 0.01, 0.008, 0.005 and 0.005 microM for CPT-11 lactone, CPT-11 carboxylate, SN-38 lactone and SN-38 carboxylate, respectively. The method was successfully used in the study on the effect of coadministered thalidomide on the plasma pharmacokinetics of CPT-11 and SN-38 in rats. Coadministered thalidomide (100mg/kg body weight by intraperitoneal injection) significantly increased the AUC(0-10h) values of CPT-11 lactone and CPT-11 carboxylate by 32.6% and 30.3 %, respectively, (P < 0.01), but decreased the values by 19.2% and 32.4% for SN-38 lactone and carboxylate, respectively, (P < 0.05). Accordingly, the value of total body clearance (CL) of CPT-11 lactone was significantly lower in combination group compared to the control (1.329 versus 1.837 L/h/kg, P = 0.0002). Plasma t(1/2beta) values for SN-38 lactone and carboxylate were significantly (P < 0.01) smaller in rats with coadministered thalidomide, as compared to rats receiving CPT-11 alone. Further studies are needed to explore the underlying mechanisms for the observed kinetic interaction between CPT-11 and thalidomide.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, Singapore 117543, Singapore.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.forename: Zeping
authors.initials: Z
authors.lastname: Hu
authors.forename: Sui Yung
authors.initials: SY
authors.lastname: Chan
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.forename: Eli
authors.initials: E
authors.lastname: Chan
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000032:analysis*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000077146:Irinotecan; D007783:Lactones / Q000032:analysis*; D000644:Quaternary Ammonium Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013792:Thalidomide / Q000008:administration & dosage
chemical_list: D002264:Carboxylic Acids; D007783:Lactones; D000644:Quaternary Ammonium Compounds; D013792:Thalidomide; D000077146:Irinotecan; C009405:tetrabutylammonium; D002166:Camptothecin