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Volume 25, Issue 5
  • ISSN: 1389-2002
  • E-ISSN: 1875-5453

Abstract

Background

Paclitaxel (PTX) is a key drug used for chemotherapy for various cancers. The hydroxylation metabolites of paclitaxel are different between humans and rats. Currently, there is little information available on the metabolic profiles of CYP450 enzymes in rats.

Objective

This study evaluated the dynamic metabolic profiles of PTX and its metabolites in rats and .

Methods

Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and LC-MS/MS were applied to qualitative and quantitative analysis of PTX and its metabolites in rats, liver microsomes and recombinant enzyme CYP3A1/3A2. Ten specific inhibitors [NF (CYP1A1), FFL (CYP1A2), MOP (CYP2A6), OND (CYP2B6), QCT (CYP2C8), SFP (CYP2C9), NKT (CYP2C19), QND (CYP2D6), MPZ (CYP2E1) and KTZ (CYP3A4)] were used to identify the metabolic pathway .

Results

Four main hydroxylated metabolites of PTX were identified. Among them, 3'-p-OH PTX and 2-OH PTX were monohydroxylated metabolites identified in rats and liver microsome samples, and 6α-2-di-OH PTX and 6α-5”-di-OH PTX were dihydroxylated metabolites identified in rats. CYP3A recombinant enzyme studies showed that the CYP3A1/3A2 in rat liver microsomes was mainly responsible for metabolizing PTX into 3'-p-OH-PTX and 2-OH-PTX. However, 6α-OH PTX was not detected in rat plasma and liver microsome samples.

Conclusion

The results indicated that the CYP3A1/3A2 enzyme, metabolizing PTX into 3'-p-OH-PTX and 2-OH-PTX, is responsible for the metabolic of PTX in rats. The CYP2C8 metabolite 6α-OH PTX in humans was not detected in rat plasma in this study, which might account for the interspecies metabolic differences between rats and humans. This study will provide evidence for drug-drug interaction research in rats.

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Study on Cytochrome P450 Metabolic Profile of Paclitaxel on Rats using QTOF-MS
Current Drug Metabolism 25, 330 (2024); https://doi.org/10.2174/0113892002308509240711100502
/content/journals/cdm/10.2174/0113892002308509240711100502
/content/journals/cdm/10.2174/0113892002308509240711100502
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  • Article Type:     Research Article
Keyword(s): 2-hydroxypaclitaxel; 3'-p-hydroxypaclitaxel; CYP3A1/3A2; metabolic profile; Paclitaxel; UHPLC-Q-TOF-MS

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