Intracellular pharmacokinetics of gemcitabine its deaminated metabolite 2′2′‐difluorodeoxyuridine and their nucleotides

摘要

AimsGemcitabine (2′,2′‐difluoro‐2′‐deoxycytidine; dFdC) is a prodrug that has to be phosphorylated within the tumour cell to become active. Intracellularly formed gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP) are considered responsible for the antineoplastic effects of gemcitabine. However, a major part of gemcitabine is converted into 2′,2′‐difluoro‐2′‐deoxyuridine (dFdU) by deamination. In the cell, dFdU can also be phosphorylated to its monophosphate (dFdUMP), diphosphate (dFdUDP) and triphosphate (dFdUTP). In vitro data suggest that these dFdU nucleotides might also contribute to the antitumour effects, although little is known about their intracellular pharmacokinetics (PK). Therefore, the objective of the present study was to gain insight into the intracellular PK of all dFdC and dFdU nucleotides formed during gemcitabine treatment.