title: Determination of irinotecan and its metabolite SN-38 in rabbit plasma and tumors using a validated method of tandem mass spectrometry coupled with liquid chromatography.
abstract: New tandem mass spectrometric method coupled with liquid chromatography (LC-MS/MS) has been developed to determine the total concentration of camptothecin derivatives (irinotecan and SN-38) regardless of inter-conversion phenomenon between carboxylate and lactone forms. At first, all sample solutions were acidified for 1h in order to completely convert CPT derivatives into their lactone forms and then CPT derivatives were extracted with organic solution containing diethyl ether and ethyl acetate (2:1, v/v) just after alkalization in the range pH 8.0-8.5 in acid-treated solutions. Analytes were separated on a reverse phase C18 column (150×2.1mm) and eluted isocratically with a mobile phase which consisted of acetonitrile-methanol-buffer (0.1% formic acid, 5mM ammonium formate) (3:4:3, v/v). CPT derivatives were monitored by tandem mass spectrometry in electrospay-positive ionization and multiple reaction mode programmed to the following transitions (m/z): '587.6→167.2' of CPT-11, '393.6→349.3' of SN-38 and '349.4→ 305.2' of CPT. The method was validated to have the proper linearity (r(2)>0.99) over the range of 5-1000ng/ml of CPT-11 and 1-250ng/ml of SN-38 with good accuracy (89.8-114.3%) and precision (less than 10%). In all stability tests, concentration of CPT-11 and SN-38 had been left in the acceptable range of 88.8-110.7% when sample solutions were acidified before determination of CPT derivatives. Newly developed LC-MS/MS method was suitable for the determination of CPT derivatives of both rabbit plasma and tumor tissues in the pharmacokinetic study.
authors.affiliation: Department of Clinical Pharmacology, College of Medicine, Kosin University, Busan 602-703, Republic of Korea. Electronic address: paaranvit@kosin.ac.kr.
authors.forename: Dae J
authors.initials: DJ
authors.lastname: Park
authors.affiliation: Department of Clinical Pharmacology, College of Medicine, Kosin University, Busan 602-703, Republic of Korea.
authors.forename: Jun H
authors.initials: JH
authors.lastname: Won
authors.affiliation: Department of Clinical Pharmacology, College of Medicine, Kosin University, Busan 602-703, Republic of Korea.
authors.forename: A R
authors.initials: AR
authors.lastname: Cho
authors.affiliation: Department of Clinical Pharmacology, College of Medicine, Kosin University, Busan 602-703, Republic of Korea.
authors.forename: Hye J
authors.initials: HJ
authors.lastname: Yun
authors.affiliation: Department of Molecular Biology and Immunology, College of Medicine, Kosin University, Busan 602-703, Republic of Korea.
authors.forename: Jeong H
authors.initials: JH
authors.lastname: Heo
authors.affiliation: Department of Clinical Pharmacology, Pusan National University, Busan, 603-729, Republic of Korea.
authors.forename: Tae H
authors.initials: TH
authors.lastname: Hwhang
authors.affiliation: Department of Clinical Pharmacology, College of Medicine, Kosin University, Busan 602-703, Republic of Korea.
authors.forename: Dae H
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Clinical Pharmacology, College of Medicine, Kosin University, Busan 602-703, Republic of Korea.
authors.forename: Woo M
authors.initials: WM
authors.lastname: Kim
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism / Q000493:pharmacokinetics*; D029769:Camptotheca / Q000737:chemistry; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D000077146:Irinotecan; D057230:Limit of Detection; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011817:Rabbits; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin
keywords: Camptothecin; Irinotecan; LC–MS/MS; Rabbit; SN-38; VX2 tumor