Carbovir is a novel carbocyclic
nucleoside which has been shown to have potent in vitro activity against human immunodeficiency virus, the causative agent of
acquired immunodeficiency syndrome. Sprague-Dawley male rats were used to investigate the pharmacokinetics and bioavailability of
carbovir. Six rats received
carbovir (20 mg/kg of
body weight) through the jugular vein, and blood samples were collected through the femoral vein 2, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, 180, and 240 min after the dose. Four of these rats also received a 60-mg/kg oral dose of
carbovir, and a similar blood sampling schedule was followed. Whole-blood samples were prepared by solid-phase extraction, and the
carbovir concentration in the samples was analyzed by reversed-phase high-pressure liquid chromatography. The profile of
carbovir concentration in blood versus time after the intravenous dose was biexponential, with a very rapid distribution phase. Terminal elimination half-life was 21.4 +/- 4.37 min, and total body clearance was 55.2 +/- 13.8 ml/min per kg, which was within the range of the hepatic blood flow. The volume of distribution at steady state was 1,123 +/- 250 ml/kg. The blood/plasma ratio and the
plasma protein binding of
carbovir in rat blood were determined in vitro by ultrafiltration. The
plasma protein binding of
carbovir was only 20% and was not concentration dependent. However, the blood/plasma ratio decreased significantly as concentration increased, indicating saturable binding sites in erythrocytes. After the oral dose, the terminal half-life was 81.0 +/- 67.6 min, indicating that oral
carbovir followed "flip-flop" kinetics, with absorption being much slower than elimination of the
drug from the body. Oral bioavailability was 0.101 +/- 0.035. Double peaks were present in the concentration-time profile for each rat receiving the oral dose, indicating either a delay in stomach emptying of the
drug or slow dissolution of precipitated
carbovir in the stomach and upper small intestine.