HEPATIC DRUG CLEARANCE

肝脏代谢是最重要的途径 取消给儿童服用的许多药物。尽管有 美国有5000多万儿童，几乎所有 在儿童时期接受某种形式的药物治疗，在许多方面 肝药清除量的特性还不是很好 孩子们。这项研究将继续进行 该计划针对肝药的两个主要方面 儿童的代谢；(1)疾病和治疗相关的变化 白血病患儿肝脏药物清除量及(2) 遗传性和非遗传性药物代谢的儿童 癌症。癌症仍然是#年因疾病死亡的主要原因。 美国2岁以上的儿童，白血病是最常见的 常见和可治愈的儿童癌症类型。第一大调 我们研究的一个方面的目的是确定 儿童急性加重期抗癌药物的应用 淋巴细胞性白血病对药物处置有显著影响， 尤其是肝脏清除和蛋白质结合。三种模式 底物(安替比林、劳拉西潘和icg)用于评估 肝脏药物清除和TO的三个主要过程 评估治疗或疾病引起的变化 孩子。因为这些儿童中超过50%的人现在治愈了急性 淋巴细胞性白血病和我们已经证明的住院患者 药物清除量的差异会影响治疗反应， 这些研究之所以重要，有几个原因。第二大调 我们研究的目的是评估基因的表达。 多晶型药物氧化和N-乙酰化的测定 患有和不患有癌症的儿童。儿科多晶性药物 新陈代谢研究从来没有进行过评估和相关 基因表达与儿童是否罹患癌症 不同于不会罹患癌症的儿童。二 对成人肺癌和膀胱癌的研究表明 药物氧化或N-乙酰化的表型可能不同 然而，在罹患癌症的患者中，这种情况从来没有发生过。 在儿科癌症患者中进行评估。我们将使用两种型号 底物(右美沙芬和咖啡因)测定 儿童癌症患者的氧化和乙酰化表型 对照组为健康无癌儿童。 还将进行分子研究，以确定 可以检测到基因组中的结构缺陷，这些缺陷是 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.