Simultaneous determination of parecoxib and its main metabolites valdecoxib and hydroxylated valdecoxib in mouse plasma with a sensitive LC-MS/MS method to elucidate the decreased drug metabolism of tumor bearing mice

Autor: Yan Liu, Yuanwei Jia, Fang Zhou, Lan Yao, Xiaoliang Jin, Jingwei Zhang, Guangji Wang, Cheng Chen
Rok vydání: 2018
Předmět:
Spectrometry
Mass
Electrospray Ionization
Clinical Biochemistry
Pharmaceutical Science
030226 pharmacology & pharmacy
01 natural sciences
High-performance liquid chromatography
Sensitivity and Specificity
Analytical Chemistry
03 medical and health sciences
Mice
0302 clinical medicine
Pharmacokinetics
Cytochrome P-450 Enzyme System
Parecoxib
Tandem Mass Spectrometry
Cell Line
Tumor
Neoplasms
Drug Discovery
medicine
Animals
Humans
Prodrugs
Oxazoles
Spectroscopy
Active metabolite
Chromatography
High Pressure Liquid
Mice
Inbred BALB C
Sulfonamides
Chromatography
Cyclooxygenase 2 Inhibitors
Chemistry
010401 analytical chemistry
Selected reaction monitoring
Reproducibility of Results
Isoxazoles
Prodrug
Valdecoxib
Xenograft Model Antitumor Assays
0104 chemical sciences
Female
Drug Monitoring
Drug metabolism
medicine.drug
Zdroj: Journal of pharmaceutical and biomedical analysis. 158
ISSN: 1873-264X
Popis: Parecoxib (PX), a prodrug of valdecoxib (VX), is an injectable selective COX-2 inhibitor, and is recommended for the treatment of cancer pain. PX can be rapidly hydrolyzed into its active metabolite VX, and VX is further metabolized into hydroxylated valdecoxib (OH-VX) by cytochrome P450 enzymes. However, cancer patients have been reported to possess reduced drug metabolism ability, which might cause excessive drug accumulation. Such overdose of PX significantly increased the risk of renal safety and cardiovascular events. Therefore, it is necessary to elucidate the concentration profiles of PX and its metabolites in cancer status. In this study, a sensitive, rapid and specific LC-MS/MS method for quantification of PX, VX and OH-VX in the plasma of tumor bearing mouse was developed and validated. After protein precipitation, all the analytes were separated on an Agilent ZORBAX Extend-C18 HPLC column (2.1 × 100 mm, 3.5 μm) with gradient elution. The analytes were detected by an electrospray negative ionization mass spectrometry in the multiple reaction monitoring mode. The transition m/z 369.0 → 119.0, m/z 312.9 → 117.9, m/z 329.0 → 196.0, and m/z 307.1 → 161.3 were used for monitoring PX, VX, OH-VX and IS respectively. The calibration curves of the analytes showed good linearity over the concentration range of 3-3000 ng/mL for PX and VX, and 3-1000 ng/mL for OH-VX. Intra- and inter-batch accuracies (in terms of relative error, RE < 9.9%) and precisions (in terms of relative standard deviation, RSD < 8.8%) satisfied the standard of validation. The matrix effect, recovery and stability were also within acceptable criteria. The method was successfully applied to the pharmacokinetics study of PX in tumor bearing mice, and PX and VX levels were found elevated with the growth of tumor volume, which might increase the risk of drug overdose.
Databáze: OpenAIRE
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