Abstract:
:Decitabine (DAC), a DNA methylation inhibitor, is transported into cancer cells mainly via equilibrative nucleoside transporter 1 (ENT1) and subsequently phosphorylated by deoxycytidine kinase (dCK). We previously reported that apparent DAC uptake into cells may be described using a simple compartment model with clearance for facilitated diffusion (PS) and subsequent phosphorylation (CLmet). In the present study, time course of apparent intracellular [3H]-DAC uptake was analyzed numerically, and PS and CLmet values were calculated using the compartment model in human colon cancer HCT116 cells. PS at 0.1 μM [3H]-DAC was markedly decreased in the presence of 100 μM irinotecan or etoposide, while CLmet was markedly decreased in the presence of 100 μM cytarabine or gemcitabine. CLmet at 0.1-10 μM [3H]-DAC varied in a concentration-dependent manner and was described by Michaelis-Menten parameters Km,met and Vmax,met. In conclusion, DAC uptake mainly via ENT1 may be described by a bidirectional first-order kinetic parameter, while phosphorylation by dCK may be described by Michaelis-Menten parameters.
journal_name
Drug Metab Pharmacokinetjournal_title
Drug metabolism and pharmacokineticsauthors
Ueda K,Nakamura T,Tanaka S,Hosokawa M,Iwakawa S,Ogawara KIdoi
10.1016/j.dmpk.2019.10.002subject
Has Abstractpub_date
2020-02-01 00:00:00pages
124-130issue
1eissn
1347-4367issn
1880-0920pii
S1347-4367(19)30116-8journal_volume
35pub_type
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