PLASMA AND CEREBROSPINAL-FLUID PHARMACOKINETICS OF 5-AZA-2'-DEOXYCYTIDINE IN RABBITS AND DOGS

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (2) , 592-597
Abstract
5-Aza-2''-deoxycytidine (5-aza-dCyd) is an effective antileukemic agent. In view of the importance for an antileukemic agent to cross effectively the blood-brain-barrier, the plasma and CSF pharmacokinetics of this drug were studied in rabbits and dogs. The 5-aza-dCyd concentrations in biological fluids were determined by bioassay and high-performance liquid chromatography. 5-Aza-dCyd was administered either as an i.v. bolus or as a continuous i.v. infusion following a loading dose. Blood and CSF samples were collected at various time intervals. After an i.v. bolus, the plasma disappearance of 5-aza-dCyd was biphasic with half-lives of 5 and 43 min in rabbits and of 5 and 75 min in dogs. The apparent volume of distribution at steady-state was in the order of 800 ml/kg for both species. The total plasma clearance of the drug was 15 ml/min per kg in rabbits and 9 ml/min per kg in dogs. After a 180 min i.v. infusion, 5-aza-dCyd slow disappearance half-lives were of 39 min in rabbits and of 144 min in dogs. The 5-aza-dCyd concentrations attained in the CSF were 27 and 58% of the plateau plasma concentration in rabbits and dogs, respectively. The drug disparition from the CSF followed closely the plasma profile after an i.v. infusion with a somewhat longer half-life. 5-Aza-dCyd can cross the blood-CSF barrier effectively, producing cytotoxic concentrations in the CSF when given by i.v. infusion.