Disposition of cytosine arabinoside (NSC-63878) and its metabolites: a pharmacokinetic simulation.
A computer-based model of the pharmacokinetics of cytosine arabinoside (ara-C) and its active metabolite, ara-CTP, has been developed. This model, which is an intracellular extension of the Bischoff-Dedrick model of multi-organ pharmcokinetics gives predictions which are in agreement with the recent measurements of Chou et al on tissue concentrations of ara-CTP and Borsa et al on blood levels of ara-C. It is shown that the ara-CTP halving time in tissue is much greater than the ara-C halving time in blood because of low tissue levels of phosphatase. For a single dose at the LD10 level in mice, significant splenic DNA inhibition is calculated to occur for 26 hours, while the ara-C levels are negligible in 6 hours. The calculated duration of cytostatic effect at lower dosages (2.5 mg/kg) is 10 or 12 hours, while ara-C blood levels are negligible within 3 hours. Implications for cell kinetics and scheduling studies are also briefly described.
D000818:Animals; D003561:Cytarabine / Q000378:metabolism* / Q000494:pharmacology; D003841:Deoxycytidine; D006801:Humans; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D008954:Models, Biological; D010710:Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism
D010710:Phosphates; D003561:Cytarabine; D003841:Deoxycytidine; D000637:Transaminases; D010770:Phosphotransferases; D010744:Phosphoric Monoester Hydrolases