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

Yang, X, Hu, Z, Chan, S, Goh, B, Chan, E, Ho, P and Zhou, S 2005, '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', Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, vol. 821, no. 2, pp. 221-228.


Document type: Journal Article
Collection: Journal Articles

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
Author(s) Yang, X
Hu, Z
Chan, S
Goh, B
Chan, E
Ho, P
Zhou, S
Year 2005
Journal name Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Volume number 821
Issue number 2
Start page 221
End page 228
Total pages 8
Publisher Elsevier BV
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 0.1 M 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 μM. The limit of quantitation in rat plasma was 0.01, 0.008, 0.005 and 0.005 μM 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 (100 mg/kg body weight by intraperitoneal injection) significantly increased the AUC0-10h 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 t1/2ß 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.
Subject Basic Pharmacology
DOI - identifier 10.1016/j.jchromb.2005.05.010
ISSN 1570-0232
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