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Plasma and Cerebrospinal Fluid Pharmacokinetics of 5-Aza-2'-deoxycytidine in Rabbits and Dogs¹

Centre de Recherche Pédiatrique, Hôpital Ste-Justine [G. G. C., G. E. R., R. L. M.], and Département de Pharmacologie, Université de Montréal [G. G. C., R. L. M.], Montreal, Quebec, Canada

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, we studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of this drug 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/kg in rabbits and 9 ml/min/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. These results showed that 5-aza-dCyd can cross the blood-CSF barrier effectively, producing cytotoxic concentrations in the CSF when given by i.v. infusion.

¹ Supported by Grant 6356 from the Medical Research Council of Canada and by LEUCAN.

² Recipient of a studentship from the Conseil de la Recherche en Sante du Quebec, Quebec, Canada.

Received 3/11/82. Accepted 10/ 6/82.

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