Antiviral Activity and Pharmacokinetics of 1-(2,3-Dideoxy-2-Fluoro-β- l -Glyceropent-2-Enofuranosyl)Cytosine

Pharmacology and Pharmacokinetics of the Antiviral Agent β-d-2′,3′-Dideoxy-3′-Oxa-5-Fluorocytidine in Cells and Rhesus Monkeys

“…(Table 2), which is higher than other nucleoside RT inhibitors (2,3). Approximately 72% of the absorbed dose was recovered unchanged in the urine after oral administration in monkeys (CL R /CL T ).…”

Pharmacokinetics of the Antiviral Agent β- l -3′-Fluoro-2′,3′-Didehydro-2′,3′-Dideoxycytidine in Rhesus Monkeys

“…The areas under the concentration-time curve after oral dose (AUC oral ), maximum plasma concentration (C max ), time of maximum concentration (T max ), bioavailability, and apparent terminal phase half-life (t 1 12 and k 21 , first-order disposition rate constants between compartment 1 and compartment 2), which may otherwise be obscured by the oral absorption, and avoids reporting two sets of disposition rate constants for the same animal. However, this approach assumes that the intercompartment disposition rate constants remain consistent once the drug reaches the circulation (4,10). Initial estimates for model parameters were obtained by using parameters from similar compounds tested in rhesus monkeys (12).…”

“…The CL renal value was derived from a model fitted to the urine excretion data by using the pharmacokinetic parameters derived from the plasma data. The following equation was used: dX u /dt ϭ CL renal ϫ C p , where dX u is the rate of renal accumulation of compound during time interval dt, and C p is the predicted concentration of the drug in the plasma based on the plasma data coinciding with the urine collection interval (4). No weighting factor was used for the urine data.…”

“…The D-analogues in the series of nucleosides related to L-3Ј-Fd4C were mostly inactive against HIV-1 (EC 90 of Ͼ10 M). However, it has been previously demonstrated that nucleosides containing modifications at the 2Ј and 3Ј positions of the sugar moiety can have potent activity against resistant mutant viruses (4,5,13,15,30). L-3Ј-Fd4C was essentially nontoxic to various cells and had no mitochondrial toxicity in HepG2 cells at concentrations up to 100 M; it was nontoxic to mice when administered intraperitoneally in a dosage of 100 mg/kg of body weight for 6 days.…”

“…The need to overcome drug-resistant mutations in viruses (7,8,14,20,22) and adverse effects during long-term human immunodeficiency (HIV) and hepatitis B virus (HBV) therapies have led to the development of several novel antiviral nucleoside agents (1,2,4,6,9,11,17,21,23,24,27,28). Pharmacokinetic studies with relevant animal models are critical to determine important pharmacokinetic parameters that are needed to develop rational starting dose regimens for clinical trials in humans.…”