Cellular pharmacokinetics of 2-chloro-2'-deoxyadenosine nucleotides: comparison of intermittent and continuous intravenous infusion and subcutaneous and oral administration in leukemia patients.

Abstract

2-Chloro-2'-deoxyadenosine (CdA) is a new purine nucleoside analogue with major activity in lymphoproliferative diseases. Its intracellular nucleotides, in particular the 5'-triphosphate, are thought to be the pharmacologically active metabolites. The present study was undertaken to elucidate the cellular pharmacokinetics of these active metabolites in leukemia patients during CdA treatment. The concentrations of CdA in plasma and of CdA nucleotides (CdAN) in leukemic cells were measured by liquid chromatography in 69 patients with chronic lymphocytic, acute myeloid, and hairy cell leukemia after intermittent and continuous i.v. infusion, s.c. injection, and p.o. administration. The t1/2 of CdAN during the first dose interval was 13.8 h (n = 67), while after the last dose the t1/2 was 32.7 h (n =8). The area under the concentration versus time curve was similar after intermittent and continuous infusion, 268.3 and 237.8 &mgr;m/h, respectively (n = 7). The area under the concentration versus time curve after p.o. administration (0.24 mg/kg) was slightly lower than that after intermittent infusion (0.12 mg/kg), 120.6 versus 188.8 &mgr;m/h (P < 0.05, n = 7). However, when all p.o. administrations (n = 16) were compared with all 2-h infusions in other patients with chronic lymphocytic leukemia (n = 32), there was no significant difference (149.6 versus 168.6 &mgr;m/h). The cellular concentration of CdAN was 320 times higher than the plasma concentration of CdA, but there was no correlation in individual patients (r2 = 0.02, n =69). The t1/2 of CdAN was significantly shorter in patients with acute leukemias (9 h) compared to those with chronic lymphocytic (12.9 h) and hairy cell leukemias (15.1 h). The area under the concentration versus time curve of CdAN in leukemic cells from the 11 patients with hairy cell leukemia given CdA s.c. was in the same range (179.8 &mgr;m/h) as in patients with chronic lymphocytic leukemia. The retention of CdAN in leukemic cells supports intermittent administration. The lack of correlation between cellular and plasma drug concentrations indicates that plasma drug concentrations are not useful for individualization of dose.