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Molecules 2018, 23(5), 1195; https://doi.org/10.3390/molecules23051195

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

College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou Industrial Park, Suzhou 215000, China
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Received: 18 April 2018 / Revised: 14 May 2018 / Accepted: 15 May 2018 / Published: 16 May 2018
(This article belongs to the Section Medicinal Chemistry)
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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 further investigation. View Full-Text
Keywords: gemcitabine; monophosphate prodrug; in vitro metabolism; CYP4F2; drug interactions gemcitabine; monophosphate prodrug; in vitro metabolism; CYP4F2; drug interactions
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Wang, Y.; Li, Y.; Lu, J.; Qi, H.; Cheng, I.; Zhang, H. Involvement of CYP4F2 in the Metabolism of a Novel Monophosphate Ester Prodrug of Gemcitabine and Its Interaction Potential In Vitro. Molecules 2018, 23, 1195.

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