Involvement of CYP4F2 in the Metabolism of a Novel Monophosphate Ester Prodrug of Gemcitabine and Its Interaction Potential In Vitro

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Yedong WangHongjian Zhang

Abstract

Compound-3 is an oral monophosphate prodrug of gemcitabine. Previous data showed that Compound-3 was more potent than gemcitabine and it was orally active in a tumor xenograft model. In the present study, the metabolism of Compound-3 was investigated in several well-known in vitro matrices. While relatively stable in human and rat plasma, Compound-3 demonstrated noticeable metabolism in liver and intestinal microsomes in the presence of NADPH and human hepatocytes. Compound-3 could also be hydrolyzed by alkaline phosphatase, leading to gemcitabine formation. Metabolite identification using accurate mass- and information-based scan techniques revealed that Compound-3 was subjected to sequential metabolism, forming alcohol, aldehyde and carboxylic acid metabolites, respectively. Results from reaction phenotyping studies indicated that cytochrome P450 4F2 (CYP4F2) was a key CYP isozyme involved in Compound-3 metabolism. Interaction assays suggested that CYP4F2 activity could be inhibited by Compound-3 or an antiparasitic prodrug pafuramidine. Because CYP4F2 is a key CYP isozyme involved in the metabolism of eicosanoids and therapeutic drugs, clinical relevance of drug-drug interactions mediated via CYP4F2 inhibition warrants furth...Continue Reading

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Citations

May 24, 2019·Chemical Communications : Chem Comm·Yuan MaChuan Zhang
Sep 5, 2019·International Journal of Molecular Sciences·Yazun Bashir Jarrar, Su-Jun Lee

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Methods Mentioned

BETA
deamination
xenograft

Software Mentioned

Systat
SigmaPlot
GraphPad Prism
GraphPad
Analyst

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