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.
Highlights
Over the last several decades, a number of nucleos(t)ide analogs have been successfully developed as antiviral, anticancer and antiplatelet drugs
Because cytochrome P450 4F2 (CYP4F2) is a key Cytochrome P450 (CYP) isozyme involved in the metabolism of eicosanoids and therapeutic drugs, clinical relevance of drug-drug interactions mediated via CYP4F2 inhibition warrants further investigation
Compound-3 was orally active in the H460 tumor xenograft model and its cellular uptake had a low propensity to be limited by human equilibrative transporter 1, a nucleoside transporter that has been implied in gemcitabine transmembrane transport and certain tumor resistance [12]
Summary
Over the last several decades, a number of nucleos(t)ide analogs have been successfully developed as antiviral, anticancer and antiplatelet drugs. Because unsubstituted nucleos(t)ides are often polar compounds with low membrane permeability, the prodrug strategy has been employed frequently to enhance pharmaceutical properties (such as permeability, metabolic stability and oral bioavailability), efficacy via organ-specific delivery, and safety via reduced formation of toxic metabolites [1]. One of the most successful prodrugs is sofosbuvir (GS-7977), a phosphoramidate prodrug of the β-d-20 -deoxy-20 -α-fluoro-20 -β-C-methyluridine nucleoside [2] Another example among the antiviral agents is tenofovir alafenamide, a prodrug of (R)-9-(2-phosphonomethoxypropyl) adenine (tenofovir) [3]. Compound-3 was orally active in the H460 tumor xenograft model (non-small cell lung cancer) and its cellular uptake had a low propensity to be limited by human equilibrative transporter 1 (hENT1), a nucleoside transporter that has been implied in gemcitabine transmembrane transport and certain tumor resistance [12]. CYP4F2 mediated interaction between Compound-3 and pafuramidine was investigated
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