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Carboxylesterase and UDP‐glucuronosyltransferases mediated metabolism of irinotecan: In vitro and in vivo insights from quantitative ultra‐performance liquid chromatography–mass spectrometry analysis
Author(s) -
Qin Yifeng,
Kang An,
Zhou Guisheng,
Wang Huan,
Wei Wei,
Cao Yujie,
Chen Yanyan,
Wang Jing,
Shi Yajun,
Tang Yuping,
Jiang Jianqin
Publication year - 2018
Publication title -
biomedical chromatography
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.4
H-Index - 65
eISSN - 1099-0801
pISSN - 0269-3879
DOI - 10.1002/bmc.4320
Subject(s) - irinotecan , carboxylesterase , chemistry , pharmacokinetics , in vivo , chromatography , pharmacology , active metabolite , sn 38 , in vitro , drug metabolism , metabolite , metabolism , biochemistry , enzyme , biology , genetics , colorectal cancer , microbiology and biotechnology , cancer
Carboxylesterase and UDP‐glucuronosyltransferase‐mediated metabolism of irinotecan (CPT‐11) has long been proposed to be responsible for its anti‐tumor activity and toxicity, like delayed‐onset diarrhea. However, recent studies failed to gain more comprehensive in vivo and in vitro pharmacokinetic profiles of irinotecan. Herein, we use rat plasma, human liver microsomes and immortalized HepG2 cell as experimental subjects to describe a sensitive and versatile UHPLC–MS/MS method for simultaneously quantifying CPT‐11 and its metabolites, including SN‐38 and SN‐38G. The method was applied to investigate the pharmacokinetic and metabolic behavior of CPT‐11 in the biological samples. Calibration curves for all bio‐matrices showed acceptable linearity ( r 2 > 0.99). The intra‐ and inter‐day precisions (RSD, %) were within 15% and the excellent accuracy (RE) was between 2.96 and 14.12%. In addition, the specificity, matrix effect and extraction recovery all met the requirements of biological sample analysis. We successfully applied this method to investigate the pharmacokinetics of irinotecan in various biological samples, mediated by carboxylesterase and UDP‐glucuronosyltransferase. This method could be employed in monitoring the metabolic status and clinical efficacy of irinotecan in the future.