Pharmacokinetics of 2',3'-dideoxy-5-fluoro-3'-thiacytidine in rats

Although several drugs have shown clinical anti-human immunodeficiency virus activity, reduced activity with long-term use and toxicity make new agents with high therapeutic indices desirable. Racemic cis-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) is a new synthetic nucleoside analogue that is usually potent against human immunodeficiency virus types 1 and 2 and hepatitis B virus in vitro. The purpose of this study was to characterize the preclinical pharmacokinetics of FTC in rats. Rats were administered 10, 50, and 100 mg of FTC per kg of body weight intravenously. Concentrations of FTC in plasma and urine were determined by HPLC. Pharmacokinetic parameters were generated by area/moment analysis. Plasma FTC concentrations declined rapidly in a biexponential fashion, with a terminal half-life of approximately 2 h. The area under the plasma FTC concentration-time curve increased proportionally with increasing dose, and there were no statistically significant differences in pharmacokinetic parameters among the three doses. Thus, the disposition of FTC was independent of dose over the range of 10-100 mg/kg. Since the disposition of FTC was linear, pharmacokinetic parameters were averaged for the three doses. The average total clearance of FTC was 1.91 +/- 0.32 L/h/kg (mean +/- SD), the average renal clearance was 1.08 +/- 0.26 L/h/kg, and the average nonrenal clearance was 0.83 +/- 0.27 L/h/kg. Approximately 55% of the dose of FTC was recovered as unchanged drug in the urine. The steady-state volume of distribution of FTC averaged 2.17 +/- 0.59 L/kg.