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Identification of the Novel Capecitabine Metabolites in Capecitabine-Treated Patients with Hand-Foot Syndrome
- Source :
- Chemical Research in Toxicology. 31:1069-1079
- Publication Year :
- 2018
- Publisher :
- American Chemical Society (ACS), 2018.
-
Abstract
- Hand-foot syndrome (HFS), the most common side effect of capecitabine, is a dose-limiting cutaneous toxicity with only rare therapeutic options. The causative mechanisms of HFS are still unclear. Many studies suggested that capecitabine or its metabolites caused the toxicity. This study is attempting to determine if there are any new metabolites that may be present and be linked to toxicity. For this purpose, 25 patients who ingested capecitabine orally were enrolled and divided into HFS positive and negative groups. Urine and plasma samples were collected before administration and five cycles after administration. Eleven phase I and phase II metabolites of capecitabine were detected and identified by ultraperformance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry with a metabolomic approach and MetaboLynxXS. Nine novel metabolites of capecitabine were identified herein, which were not observed in the HFS negative group. Their structures were confirmed by chemical synthesis and nuclear magnetic resonance spectroscopy. The cytotoxities of capecitabine and its metabolites on HaCaT cells were measured. Among them, M9/10 exhibited significant inhibitory activity, and they were produced via acetylation mainly by N-acetyltransferase 2. Our study comprehensively described the metabolism of capecitabine in patients with HFS and detected the novel pathways of capecitabine, which was a positive significance for the mechanism of HFS.
- Subjects :
- Male
Antimetabolites, Antineoplastic
Magnetic Resonance Spectroscopy
Side effect
Arylamine N-Acetyltransferase
Cell Survival
Administration, Oral
Urine
Pharmacology
Toxicology
Tandem mass spectrometry
Cell Line
Capecitabine
Metabolomics
Tandem Mass Spectrometry
Humans
Medicine
Least-Squares Analysis
Chromatography, High Pressure Liquid
integumentary system
business.industry
Discriminant Analysis
General Medicine
Metabolism
Middle Aged
HaCaT
Toxicity
Microsomes, Liver
Female
Hand-Foot Syndrome
business
medicine.drug
Subjects
Details
- ISSN :
- 15205010 and 0893228X
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- Chemical Research in Toxicology
- Accession number :
- edsair.doi.dedup.....73ab6e874e1535c677967a76e5894ffb