HEPATIC DRUG CLEARANCE

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Hepatic metabolism represents the most important pathway for elimination of many drugs given to children. Although there are more than 50 million children in the United States and almost all receive some form of drug therapy during childhood, many aspects of hepatic drug clearance have not been well characterized in children. The research will will undertake in the continuation of this program is aimed at two major aspects of hepatic drug metabolism in children; (1) disease and treatment related changes in hepatic drug clearance in children with leukemia and (2) genetic polymorphic drug metabolism in children with and without cancer. Cancer remains the leading cause of death by disease in U.S. children over 2 years of age, and leukemia is one of the most common and curable types of childhood cancer. The first major aspect of our research is aimed at determining whether the administration of anticancer drugs to children with acute lymphocytic leukemia has significant effects on drug disposition, particularly hepatic clearance and protein binding. Three model substrates (antipyrine, lorazepam and ICG) are used to assess three major processes involved in hepatic drug clearance and to evaluate treatment-or diseased-induced changes within the same child. As more than 50% of these children are now cured of acute lymphocytic leukemia and we have shown that interpatient differences in drug clearance influence therapeutic response, these studies are important for several reasons. The second major aim of our research is to evaluate the expression of genetically determined polymorphic drug oxidation and N-acetylation in children with and without cancer. Pediatric polymorphic drug metabolism studies have never been done to assess and-related expression of genotype and whether children who develop cancer are different from children who do not develop cancer. Two studies in adults with lung cancer and bladder carcinoma indicate that drug oxidation or N-acetylation phenotype may be different in patients who develop cancer, however, this has never been assessed in pediatric cancer patients. We will use two model substrates (dextromethorphan and caffeine) to determine oxidation and acetylation phenotype in children with cancer and a matched control group of healthy children without cancer. Molecular studies will also be undertaken to determine if structural defects in the genome can be detected which are associated with metabolic phenotype. Collectively, this research will add considerable new knowledge to our understanding of drug metabolism in children.