Pharmacokinetics of beta-L-2',3'-dideoxy-5-fluorocytidine in rhesus monkeys.
beta-L-2',3'-Dideoxy-5-fluorocytidine (beta-L-FddC), a novel cytidine analog with an unnatural beta-L sugar configuration, has been demonstrated by our group and others to exhibit highly selective in vitro activity against human immunodeficiency virus types 1 and 2 and hepatitis B virus. This encouraging in vitro antiviral activity prompted us to assess its pharmacokinetics in rhesus monkeys. Three monkeys were administered an intravenous dose of [3H] beta-L-FddC at 5 mg/kg of body weight. Following a 3-month washout period, an equivalent oral dose was administered. Plasma and urine samples were collected at various times for up to 24 h after dosing, and drug levels were quantitated by high-pressure liquid chromatography. Pharmacokinetic parameters were obtained on the basis of a two-compartment open model with a first-order elimination from the central compartment. After intravenous administration, the mean peak concentration in plasma (Cmax) was 29.8 +/- 10.5 microM. Total clearance, steady-state volume of distribution, terminal-phase plasma half-life (t1/2 beta), and mean residence time were 0.7 +/- 0.1 liters/h/kg, 1.3 +/- 0.1 liters/kg, 1.8 +/- 0.2 h, and 1.9 +/- 0.2 h, respectively. Approximately 47% +/- 16% of the intravenously administered radioactivity was recovered in the urine as the unchanged drug with no apparent metabolites. beta-L-FddC exhibited a Cmax of 3.2 microM after oral administration, with a time to peak drug concentration of approximately 1.5 h and a t1/2 of 2.2 h. One monkey in the oral administration arm of the study had a significant delay in the absorption of the aqueous administered dose. The absolute bioavailability of orally administered beta-L-FddC ranged from 56 to 66%.
Martin
L T
LT
Department of Clinical Pharmacology, University of Alabama, Birmingham 35294, USA.
Cretton-Scott
E
E
Schinazi
R F
RF
Zhou
X J
XJ
McClure
H M
HM
Mathe
C
C
Gosselin
G
G
Imbach
J L
JL
Sommadossi
J P
JP
D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007700:Kinetics; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
D019380:Anti-HIV Agents; C085719:2',3'-dideoxy-beta-5-fluorocytidine; D016047:Zalcitabine