HEPATIC DRUG CLEARANCE

肝脏代谢是最重要的途径， 消除了许多给儿童服用的药物。 虽然有 在美国有超过5000万儿童， 在儿童时期接受某种形式的药物治疗， 肝脏药物清除率尚未得到充分表征， 孩子 这项研究将继续进行。 该计划针对肝脏药物的两个主要方面 儿童代谢;（1）疾病和治疗相关变化 在白血病儿童的肝脏药物清除率和（2） 遗传多态性药物代谢的儿童与非儿童 癌 癌症仍然是导致死亡的主要疾病， 美国2岁以上的儿童，白血病是最常见的疾病之一。 常见且可治愈的儿童癌症。 第一主 我们的研究的一个方面是为了确定是否 儿童急性白血病的抗癌药物治疗 淋巴细胞白血病对药物处置有显著影响， 特别是肝清除和蛋白结合。 三个模型 底物（安替比林，劳拉西泮和ICG）用于评估 肝脏药物清除的三个主要过程， 评价治疗或疾病引起的变化， 孩子 由于超过50%的这些儿童现在治愈了急性 淋巴细胞白血病，我们已经证明， 药物清除率的差异影响治疗反应， 这些研究之所以重要，有几个原因。 第二主 我们研究的目的是评估基因表达， 测定的多晶型药物氧化和N-乙酰化 患有和未患癌症的儿童。 儿科多晶型药物 代谢研究从来没有做过评估和相关的 基因型的表达和儿童是否患癌症 与未患癌症的儿童不同。 两 对成人肺癌和膀胱癌患者的研究表明， 药物氧化或N-乙酰化表型可能不同， 然而，在患癌症的患者中， 在儿科癌症患者中进行评估。 我们将使用两个模型 底物（美沙芬和咖啡因），以确定 氧化和乙酰化表型的儿童癌症和 对照组为健康无癌儿童。 分子研究也将进行，以确定是否 可以检测到基因组中的结构缺陷， 与代谢表型相关。 总的来说，这项研究 将为我们对药物的理解增加相当多的新知识， 儿童的新陈代谢。

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.