The pharmacokinetic parameters of
cladribine (CdA) in patient plasma and its intracellular
nucleotides CdA 5'-monophosphate (
CdAMP) and CdA 5'-triphosphate (CdATP) were delineated in circulating
leukemia cells in 17 patients with
chronic lymphocytic leukemia, after the last dose intake and up to 72 h thereafter. Patients were treated with 10 mg/m2 CdA p.o. on 3 consecutive days. A novel and specific ion-pair liquid chromatographic method, which separates the intracellular CdA
nucleotides, was used. The area under the concentration versus time curve (AUC) of
CdAMP in
leukemia cells was generally higher (median, 47 micromol/liter x h) than the AUC of CdATP (median, 22 micromol/liter x h); however, in some patients (3 of 17), the reverse relationship was seen. The median ratio between the AUC values for CdATP and
CdAMP was 0.60 (95% confidence interval, 0.4-1.0). The median half-life (t(1/2)) of
CdAMP was 15 h, and that of CdATP was 10 h. The median terminal t(1/2) of CdA in plasma was 21 h. A significant correlation was found between the maximum plasma CdA and cellular
CdAMP concentrations (r = 0.56, P = 0.02). There was no correlation between the AUC values of cellular
CdAMP and CdATP (r = 0.224, P = 0.55). No correlation was found between
deoxycytidine kinase activity and intracellular pharmacokinetic parameters of
CdAMP or CdATP. The response to treatment was not significantly related to intracellular concentration of
CdAMP or active metabolite CdATP. There is great heterogeneity among patients in terms of AUC and t(1/2) of
CdAMP and CdATP. Furthermore, the results emphasize the differences between the pharmacokinetics of plasma CdA and those of the metabolites in circulating leukemic cells.