PHARMACOKINETICS OF CLADRIBINE IN PLASMA AND ITS 5'-MONOPHOSPHATE AND5'-TRIPHOSPHATE IN LEUKEMIC-CELLS OF PATIENTS WITH CHRONIC LYMPHOCYTIC-LEUKEMIA

The pharmacokinetic parameters of cladribine (CdA) in patient plasma a nd its intracellular nucleotides CdA 5'-monophosphate (CdATP) 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/m(2 ) CdA p.o. on 3 consecutive days, A novel and specific ion-pair liquid chromatographic method, which separates the intracellular CdA nucleot ides, was used, The area under the concentration versus time curve (AU G) of CdAMP in leukemia cells was generally higher (median, 47 mu mol/ liter.h) than the AUC of CdATP (median, 22 mu mol/liter.h); however, i n some patients (3 of 17), the reverse relationship was seen, The medi an ratio between the AUC values for CdATP and CdAMP was 0.60 (95% conf idence 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 maxi mum 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 deoxycy tidine kinase activity and intracellular pharmacokinetic parameters of CdAMP or CdATP, The response to treatment was not significantly relat ed 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 differenc es between the pharmacokinetics of plasma CdA and those of the metabol ites in circulating leukemic cells.