This research project has been developed because several previous studies in animals and preliminary studies in humans indicate that cancer chemotherapy can substantially alter the liver's ability to metabolize drugs. The long term objectives of this research proposal are (1) to determine whether treatment of acute lymphocytic leukemia in children causes either acute or chronic changes in hepatic clearance of drugs, and whether these changes are influenced by the intensity and duration of cancer chemotherapy, and (2) to improve the use of drugs in all children by identifying and characterizing patient variables which correlate with three major processes responsible for hepatic clearance of drugs (microsomal metabolism, conjugation and liver blood flow). Specifically, acute and chronic changes in the hepatic clearance of three """"""""test drugs"""""""" (antipyrine, lorazepam and indocyanine green) will be assessed in a longitudinal study of three groups of children; a control group of children who do not receive cancer chemotherapy, a second group of children with leukemia who receive a contemporary cure-oriented chemotherapy regimen and a third group of children with leukemia who receive a recently developed and more intensive regimen of cancer chemotherapy. All children are evaluated prior to receiving any cancer therapy, immediately after remission induction therapy, and approximately every six months while receiving maintenance chemotherapy (2.5 years), then annually after all chemotherapy has been stopped. At the time of each evaluation, the three test drugs are simultaneously given as an intravenous infusion, and the clearance (and other pharmacokinetic parameters) of each is determined from serial plasma concentrations of each drug, after high-performance liquid chromatographic analysis. The proposed methods allow qualitative and quantitative assessment of both acute and chronic cancer chemotherapy induced changes in hepatic clearance of drugs in these children, with comparison to an age-matched control group who do not receive cancer chemotherapy. In those patients developing altered drug clearance, the nature of these changes will be assessed by measuring changes in specific mechanisms responsible for hepatic drug clearance, such as fractionated antipyrine clearances, in vitro hepatic microsomal content and activity, and histopathological characterization of liver biopsy/autopsy specimens. The influence of duration of remission induction and the intensity and duration of remission maintenance chemotherapy will also be assessed. Data obtained from the control group and the children with leukemia prior to therapy will be utilized to determine which demographic or biological characteristics correlate with the rate of hepatic clearance of the three test drugs in children. Results of the proposed study should be useful in designing future (less toxic) treatment programs for childhood leukemia and should have broad applications to all pediatric patients by characterizing age-related changes in major processes responsible for hepatic drug clearance in children.
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