PHARMACOKINETICS OF HIGH-DOSE CYTARABINE AND ITS DEAMINATION PRODUCT-A REAPPRAISAL

Cytarabine is intracellularly activated and correlations have been est ablished between the pharmacokinetic behaviour of active metabolites a nd their antileukemic effect. Recently, a good response to high-dose t reatment of leukemias has additionally been attributed to a so-called low deamination phenotype of cytarabine inactivation. Consequently, th ese findings would support plasma level monitoring of cytarabine and i ts metabolite uracil arabinoside in high-dose cytarabine regimens. Thi s pharmacokinetic study presents data attempting to reevaluate these o bservations. Thirty-seven patients were treated by 3-h high-dose cytar abine infusions (9 patients 1000 mg/m(2), 28 patients 3000 mg/m(2)) as part of their treatment for acute leukemia. Serial blood samples duri ng and post infusion were analysed for cytarabine (araC) and its deami nation product uracil arabinoside (araU) using HPLC with UV-detection. Considerable interindividual variation was observed in end-infusion p lasma concentrations of araC (1000 mg/m(2): 2.1-fold, 3000 mg/m(2): 5. 5-fold) and araU (1000 mg/m(2): 2.7-fold, 3000 mg/m(2): 2.9-fold). The median ratio of end infusion concentrations araU/araC (on a molar bas is) was 5.6 (S.D. 3.0), extreme ratio values were 2 and 14. No differe nces of the araU/araC ratio were found between the two dosages used. M inimum plasma araC concentrations at the end of infusion were 10.5 mu mol/l and 22.0 mu mol/l at a dose of 1000 and 3000 mg/m(2), respective ly. In our European study population a ''fast'' deamination phenotype of cytarabine (araU/araC ratio > 14) was not be observed.