The disposition of cytosine arabinoside and its metabolite after single doses to rabbits.
Cytosine arabinoside (ara-C) is rapidly deaminated in 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 +/- 0.16 l kg-1 (mean +/- SD) and was significantly smaller (p less than 0.05) than that of ara-U (1.22 +/- 0.70 l 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 +/- 0.05 l h-1). In the rabbits that received both treatments (n = 7), the fraction of the ara-C dose metabolized to ara-U (fm) 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.
Zimmerman
C L
CL
University of Minnesota, College of Pharmacy, Minneapolis 55455.
D000818:Animals; D001086:Arabinofuranosyluracil / Q000493:pharmacokinetics; D003561:Cytarabine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007275:Injections, Intravenous; D008297:Male; D011817:Rabbits
D003561:Cytarabine; D001086:Arabinofuranosyluracil