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Study on Cytochrome P450 Metabolic Profile of Paclitaxel on Rats using QTOF-MS.
Meng, Zhaoyang; Chen, Junjun; Xu, Lingyan; Xiao, Xiao; Zong, Ling; Han, Yonglong; Jiang, Bo.
Afiliación
  • Meng Z; Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yi Shan Road, Shanghai, 200233, P. R. China.
  • Chen J; College of Food Science and Technology, Shanghai Ocean University, 999 Hucheng Huan Road, Shanghai, 201306, P. R. China.
  • Xu L; Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yi Shan Road, Shanghai, 200233, P. R. China.
  • Xiao X; Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yi Shan Road, Shanghai, 200233, P. R. China.
  • Zong L; Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yi Shan Road, Shanghai, 200233, P. R. China.
  • Han Y; Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yi Shan Road, Shanghai, 200233, P. R. China.
  • Jiang B; Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yi Shan Road, Shanghai, 200233, P. R. China.
Curr Drug Metab ; 25(5): 330-339, 2024.
Article en En | MEDLINE | ID: mdl-39039675
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 in vitro.

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 in vitro.

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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Microsomas Hepáticos / Paclitaxel / Ratas Sprague-Dawley / Sistema Enzimático del Citocromo P-450 Límite: Animals Idioma: En Revista: Curr Drug Metab Asunto de la revista: METABOLISMO / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Microsomas Hepáticos / Paclitaxel / Ratas Sprague-Dawley / Sistema Enzimático del Citocromo P-450 Límite: Animals Idioma: En Revista: Curr Drug Metab Asunto de la revista: METABOLISMO / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos