The disposition of cytosine arabinoside and its metabolite after single doses to rabbits

Cytosine arabinoside (ara‐C) is rapidly deaminated vivo to ara‐U by cytidine‐deoxycytidine deaminase. The purpose of this study was to determine the contribution of the deamination pathway to the overall clearance of ara‐C after a single dose to rabbits, as well as to determine the pharmacokinetics of ara‐U itself. Male rabbits were cannulated in the marginal ear vein and received a single IV bolus dose (50 mg kg ⁻¹) of either ara‐C (n=10) or ara‐U (n=10). Blood samples were collected for up to 24 h. One week later, the rabbits received the opposite treatment. Plasma samples were analyzed by reversed‐phase HPLC. The plasma clearance of ara‐C (8·16 ± 2·43 ml min⁻¹ kg⁻¹) was significantly higher than the clearance of ara‐U (5·66 ± 2·59 ml min⁻¹ kg⁻¹). The volume of distribution of ara‐C was 0·64 ± 0·161 kg⁻¹ (mean ± SD) and was significantly smaller (p <0.05) than that of ara‐U (1·22 ± 0·701 kg⁻¹). As a result, the elimination rate constant of ara‐C was significantly larger than that of ara‐U (0·602 ± 0·097 h⁻¹ vs 0·258 ± 0·051 h⁻¹). In the rabbits that received both treatments (n=7), the fraction of the ara‐C dose metabolized to ara‐U (f^m) was 0·53 ± 0·20. Qualitatively, the pharmacokinetics of ara‐C and ara‐U resemble those in humans. This study provides the basis for further work into the modulation of ara‐C disposition either by ara‐U or other agents.