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

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.

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

“…CYP2A6 is associated with the efficacy of SOX (S-1 plus oxaliplatin) regimen [40], and CYP4F2 partakes in the metabolism of gemcitabine [41]. with a high degree of heterogeneity [17,18].…”

Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications

“…The roles of most CYP4 family proteins in the metabolism of drugs and xenobiotic compounds appear to be minor compared to those of CYP1, 2, and 3. However, CYP4F2 metabolizes the ester prodrug of gemcitabine and the antiparasitic pafuramidine [57]. In addition, CYP4A11 exhibited metabolism of the immune suppressant tacrolimus to an inactive form [58].…”

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

“…Because that the path: 00982_1 subpathway is composed of four groups of enzymes ( Supplementary Table S2) [25], we further studied these enzymes and tried to seek the association with the above chemotherapeutic drugs. CYP2A6 participates in the metabolism of fluorouracil and CYP3A4 is involved with irinotecan pharmacokinetics [39], CYP2A6 is associated with the efficacy of SOX (S-1 plus oxaliplatin) regimen [40], and CYP4F2 partakes in the metabolism of gemcitabine [41]. However, majority of molecules in this subpathway are unable individually to exhibit a significant predictive ability (Analytical Data File 7) by using a univariate Cox method to evaluate the correlation between each gene and the survival of PDAC patients.…”