The Disposition of Ara-C and Its Metabolites

A Pharmacokinetic Simulation

by Paul F. Morrison, Thomas L. Lincoln, Jerry Aroesty

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Describes a computer model of the pharmacokinetics of anticancer agents, and applies it to the drug cytosine arabinoside (ara-C), a major factor in the improved survival rate for adult leukemia. Although the model is applicable to any species, the authors concentrate on applying it to the experimental therapeutics of mouse leukemia. They show that ara-CTP — the metabolite of ara-C that is known to kill dividing cells or severely inhibit their rate of DNA synthesis — is present in tissue, after a single injection of ara-C, for times that are much longer than those estimated from ara-C levels alone. Thus, since the kinetics of ara-C and ara-CTP [in vivo] are quite different, the use of ara-C concentrations to predict states of the ara-CTP-dependent properties of toxicity or DNA inhibition can lead to large errors. The study also elaborates on the need for further measurements of certain enzyme levels (phosphatase) that are determinants of long ara-CTP halving time.

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