On the Cellular Pharmacokinetics of 6-Thioguanine in Acute Myelogenous Leukemia

Publisher Website
Google Scholar
Abstract
The pharmacokinetics of 6-thioguanine were studied in 10 patients with acute myelogenous leukemia treated with 25-100 mg/m(2) orally. The concentration of 6-thioguanine in plasma was determined with reversed phase high performance liquid chromatography (HPLC). After isolation of leukemic cells and erythrocytes by density centrifugation, HClO4 extraction of nucleotides and isolation of thiol containing substances on mercurial cellulose, the intracellular concentration of phosphorylated 6-thioguanine metabolites was measured by anion exchange HPLC. The plasma peak concentration of 6-thioguanine was significantly correlated (r(2) = 0.60) to the dose administered. In the leukemic cells, the 5'-mono-(TGMP) and 5'-triphosphates (TGTP) of 6-thioguanosine could be detected in nine of the patients. In one patient only TGMP was seen. The diphosphate could be detected in low concentrations in 6 patients. In all patients, the concentration of TGMP was higher than that of TGTP which was higher than the diphosphate. The interindividual variation in cellular TGMP and TGTP concentration was > 100-fold and independent of dose, while the variation in plasma 6-TG was < 15-fold. There was no correlation between dose or plasma area under the concentration versus time curve (AUC) of 6-TG and the cellular AUC of TGMP or TGTP. However, the AUC of TGMP and TGTP correlated significantly (r(2) = 0.64). The t1/2 of the intracellular metabolites and of 6-thioguanine in plasma were in the same order (4.4, 5.2 and 5.0 h for plasma 6-thioguanine, the intracellular mono- and triphosphate respectively). Phosphorylated metabolites of 6-thioguanine were detectable in erythrocytes from 8 patients. The kinetic pattern of the metabolites in erythrocytes was different from that in leukemic cells. While shortly after administration being eliminated according to first order kinetics in the leukemic cells, the concentration of intracellular metabolites in the erythrocytes was raising during the first 24 h after the treatment. The concentration of the metabolites were, however, much (100-fold) lower in erythrocytes compared to leukemic cells. Furthermore, the triphosphate was the predominant metabolite in the erythrocytes and considerable amounts of the diphosphate was seen while the concentration in the monophosphate was low. We conclude that there is a considerable interindividual variation in the cellular pharmacokinetics of TGMP and TGTP. The concentration of the phosphorylated metabolites in the leukemic cells cannot be predicted by determination of plasma 6-thioguanine concentration, nor by the concentration of the same metabolites in the erythrocytes.