2-3-dihydro-1h-imidazo(1-2-b)pyrazole and Glucosephosphate-Dehydrogenase-Deficiency

2,3 dihydro-IH-imidazo (1,2-b) pyrazole (IMPY) is a potential chemotherapeutic agent known to inhibit cellular DNA synthesis by blocking ribonucleotide reductase. During Phase I clinical studies with IMPY, patients developed a dose dependent hemolytic anemia possibly secondary to oxidant damage to the RBC. We therefore studied the effect of IMPY on the metabolism of human RBC's in vitro. IMPY, in clinically achievable concentrations, stimulated the hexose monophosphate shunt (HMPS) pathway of RBC's. This was associated with the generation of reactive oxygen species as demonstrated by the glutathione (GSH) instability and enhanced formate oxidation of RBC's incubated with the drug. In addition, the GSH concentration of the red cells of a patient fell during a continuous infusion of IMPY. These effects of IMPY on red cell metabolism in vitro and in vivo are similar to those of drugs known to cause oxidative damage to this cell. The capacity of IMPY to act as an oxidant could explain the hemolytic anemia seen in patients receiving this drug.

Topics: Antineoplastic Agents; Erythrocytes; Formates; Free Radicals; Glucosephosphate Dehydrogenase Deficiency; Glutathione; Hexoses; Humans; Hydrogen Peroxide; Kinetics; Oxidation-Reduction; Pyrazoles