Résumé
The β-
l enantiomers of 2′,3′-dideoxycytidine (β-
l-ddC) and its 5-fluoro derivative, 2′,3′-dideoxy-5-fluorocytidine (β-
l-FddC), were demonstrated to be active against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) replication
in vitro. In the present study, we investigated the cellular pharmacology of β-
l-ddC and β-
l-FddC and compared it with that of β-
d-2′,3′-dideoxy-5-fluorocytidine (β-
d-FddC). β-
lFddC (10 -μM) was found to be phosphorylated rapidly in Hep-G2 cells to its 5′-mono-, di-, and triphosphate derivatives with intracellular triphosphate levels achieving 26.6 ± 10.9 pmol/10
6 cells after 72 hr. In contrast, the active 5′-phosphorylated derivative of β-
d-FddC achieved lower levels with triphosphate levels of only 2.3 ± 0.5 pmol/10
6 cells under the same conditions. β-
l-ddC was also phosphorylated rapidly. A 5′-diphosphocholine (18.7 ± 5.8 pmol/10
6 cells) and a 5′-diphosphoethanolamine (13.6 ± 0.9 pmol/10
6 cells) derivative were detected in β-
d-FddC-treated cells after 72 hr, whereas in β-
l-FddC- and β-
l-ddC-treated cells, only the 5′-diphosphocholine derivative (10.9 ± 2.8 and 60.4 ± 5.7 pmol/10
6 cells, respectively) was detected. β-
l-FddC-5′-triphosphate (β-
l-FddCTP), β-
d-FddC-5′-triphosphate (β-
d-FddCTP), and β-
l-ddC-5′-triphosphate (β-
l-ddCTP) followed a single phase elimination process with an intracellular half-life (
T
1
2
) of 10.5, 5.7, and 12.3 hr, respectively. Furthermore, β-
l-FddCTP, β-
d-FddCTP, and β-
l-ddCTP levels of 6.7 ± 2.3, 0.3 ± 0.1, and 12.0 pmol/10
6 cells, respectively, were still detectable 24 hr following drug removal. The higher intracellular 5′-triphosphate levels of β-
l-FddC and the extended
T
1
2
of its 5′-triphosphate are consistent with the more potent
in vitro antiviral activity of β-
l-FddC in Hep-G2 cells when compared with its β-
d enantiomer, β-
dFddC.