title: The development of a quantitative and qualitative method based on UHPLC-QTOF MS/MS for evaluation paclitaxel-tetrandrine interaction and its application to a pharmacokinetic study.
abstract: Paclitaxel is a broad-spectrum anti-cancer drug by targeting microtubulin. However, multidrug resistant (MDR) makes its clinical application more difficult and results in failure of chemotherapy. Tetrandrine as a potential multidrug resistant modulator could be combined with other anti-cancer drugs. In this study, ultra-performance liquid chromatography (UHPLC) combined with quadrupole time-of-flight mass spectrometry (QTOF) was applied to simultaneously qualitative and quantitative analysis of paclitaxel for the pharmacokinetic studies while combined with tetrandrine. This method was developed based on non-target screening mode IDA (Information Dependent Acquisition). As a result, the validated range was 0.25-64ng/ml (30µl plasma) for paclitaxel. Totally 33 metabolites of paclitaxel and tetrandine were identified in vivo and in vitro. The main metabolites of PTX were dose-dependent decreased with different amounts of tetrandine co-administration no matter in vivo and in vitro, the exposure of PTX increased in pharmacokinetic study. The verified method is sensitive accurate and effective for the simultaneous determination of paclitaxel and its metabolites in blood, urine and live microsome incubation samples and it was successfully applied to evaluate the pharmacokinetics and drug-drug interaction between paclitaxel and tetrandine. Furthermore, a biosensor technology, surface plasmon resonance (SPR) analysis was applied to preliminary evaluate the competitive protein binding of multiple components. The SPR analysis indicated that the affinity between 6-hydroxy-paclitaxel and micotubulin is similar to that between paclitaxel and micotubulin, and tetrandrine also does not form a competitive combination with paclitaxel. For human, 6-hydroxy-paclitaxel is the one of main metabolites of paclitaxel, so the results suggested that tetrandine has an influence on the metabolite of paclitaxel, but tetrandine and the main metabolites of PTX probably do not affect PTX's biological targeting, the effect of its pharmacological action needs to be further studied.
authors: School of Pharmacy, Fudan University, Pudong, Shanghai, 201203, PR China; Center for Pharmacological Evaluation and Research of SIPI, Shanghai Institute of Pharmaceutical Industry, Shanghai, 200437, PR China.
authors: Dan
authors: D
authors: Li
authors: School of Pharmacy, Fudan University, Pudong, Shanghai, 201203, PR China.
authors: Zhonglian
authors: Z
authors: Cao
authors: School of Pharmacy, Fudan University, Pudong, Shanghai, 201203, PR China.
authors: Xueling
authors: X
authors: Liao
authors: School of Pharmacy, Fudan University, Pudong, Shanghai, 201203, PR China. Electronic address: yangping@fudan.edu.cn.
authors: Ping
authors: P
authors: Yang
authors: Center for Pharmacological Evaluation and Research of SIPI, Shanghai Institute of Pharmaceutical Industry, Shanghai, 200437, PR China. Electronic address: liulisipi@foxmail.com.
authors: Li
authors: L
authors: Liu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D044182:Benzylisoquinolines / Q000494:pharmacology*; D015374:Biosensing Techniques; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D017207:Rats, Sprague-Dawley; D020349:Surface Plasmon Resonance; D053719:Tandem Mass Spectrometry; D014404:Tubulin / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D014404:Tubulin; C009438:tetrandrine; D017239:Paclitaxel
keywords: Drug–drug interaction (DDI); Paclitaxel; Surface plasmon resonance (SPR); Tetrandrine; UHPLC-QTOF MS/MS