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The genetic variants in the MDR1 gene alone cannot explain the large variability in vincristine pharmacokinetics.

We studied vincristine pharmacokinetics in 70 children newly diagnosed with acute lymphoblastic leukemia, after a single dose of vincristine as monotherapy. Vincristine plasma concentrations were measured by HPLC analysis. A two-compartment, firstorder pharmacokinetic model was fitted to the data by maximum a posteriori parameter estimation. In this group of children pharmacokinetic factors were highly variable: median (25th and 75th percentiles) total body clearance, 228 (128 -360) Vincristine, one of the naturally occurring vinca alkaloids extracted from the leaves of the periwinkle plant Catharanthus roseus, continues to play a key role in the treatment of childhood ALL since its introduction in 1962 (1). Vincristine exerts an antimitotic effect (2-4) and induces apoptosis in various hematologic cell lines (5-8). Its antileukemic effect in vivo is determined by both variability in exposure of the leukemic cells and variability in sensitivity of the cells to the effect of vincristine. In vitro sensitivity of leukemic cells has been well studied (9), but the variability in exposure of leukemic cells in vivo has received less attention. Therefore, we studied vincristine pharmacokinetics in children newly diagnosed with ALL, after a single dose of vincristine.Vincristine-induced cell kill in a human lymphoblastic leukemia cell line was proportional to saturation of cellular binding sites (10), suggesting that the concentration of vincristine to which the cell is exposed is an important determinant of the antileukemic effect of vincristine. In vitro, vincristine accumulates in cells to concentrations as high as 500 times extracellular concentrations and is slowly released from the cells after restoration in drug-free medium (11, 12). Tissue distribution of vincristine was studied with 3 H-labeled vincristine in the rat and revealed accumulation in spleen, adrenal and thyroid glands, large and small intestines, heart, lung, kidney, liver, and marrow. Penetration in rat eye, fat, and brain tissue and in human cerebrospinal fluid appears to be very poor (13)(14)(15).The first pharmacokinetic studies on vincristine in man were performed when 3 H-labeled vincristine became available, 15 y after the introduction of vincristine in clinical practice. It was found that urinary excretion accounts for up to 12% of excreted radioactivity (16, 17). The biliary system appeared to be the principal route of excretion (13, 18 -20

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