Genetic predictors of thiazolidinedione response

噻唑烷二酮反应的遗传预测因子

• 批准号: 7458819
• 负责人: CHRISTINA L AQUILANTE
• 金额: $ 12.01万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-10 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458819
• 关键词: 2,4-thiazolidinedione; Address; Affect; African American; Area; Caucasians; Caucasoid Race; Class; Clinical; Clinical Pharmacology; Cytochrome P450; Data; Development; Diabetes Mellitus; Drug Interactions; Drug Kinetics; Drug Metabolism Inhibition; Enzyme Gene; Enzymes; Ethnic group; Fasting; Future; Gemfibrozil; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glucose; Goals; Hepatic; Human; Hypoglycemic Agents; Mediating; Medicine; Metabolic; Metabolism; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacotherapy; Pioglitazone; Plasma; Purpose; Race; Research; Research Personnel; Single Nucleotide Polymorphism; Thiazolidinediones; Toxic effect; career; diabetic; drug efficacy; programs; response; rosiglitazone

DESCRIPTION (provided by applicant): The field of pharmacogenetics is aimed at understanding how genetic variation contributes to variability in drug efficacy or toxicity. Agents in the thiazolidinedione (TZD) drug class, pioglitazone and rosiglitazone, are used commonly in the treatment of type 2 diabetes. Currently, it is unknown whether genetic variation influences TZD disposition (pharmacokinetics) and response (pharmacodynamics) in humans. Furthermore, few studies have evaluated whether genetics influences the magnitude of inhibitory drug-drug interactions in diabetes clinical pharmacology. The studies proposed within this application will focus on genetic variation within the cytochrome P450 2C8 (CYP2C8) metabolizing enzyme gene. CYP2C8 is responsible for the hepatic metabolism of TZDs. Polymorphisms within this gene decrease the activity of the metabolizing enzyme. The extent to which CYP2C8 polymorphisms influence TZD pharmacokinetics or pharmacodynamics in humans has not been fully elucidated. We will determine if genetic polymorphisms in the CYP2C8 gene contributes to variability in pioglitazone pharmacokinetics and pharmacodynamics in Caucasian and African American patients with type 2 diabetes. Like drug disposition and response, interindividual variability also exists in the magnitude of pharmacokinetic changes caused by inhibitory drug-drug interactions. Drug interactions are germane to diabetes pharmacotherapy because inhibition of drug metabolism may enhance the efficacy or toxicity of the hypoglycemic agent. The studies in this application will investigate gemfibrozil-mediated CYP2C8 inhibition of pioglitazone metabolism. We will determine if CYP2C8 polymorphisms affect the extent to which gemfibrozil alters pioglitazone metabolism and pharmacokinetics in humans. In doing so, we will target an important, but poorly defined area, of diabetes clinical pharmacology. The long term objective of this line of research is to more comprehensively characterize the contribution of genetics to interindividual variability in TZD disposition, response, and drug interactions. The goal of diabetes pharmacogenetic research is to better understand how a person's genetic make-up influences response to diabetes medications. In the future, this information may be used to aid in the selection of appropriate drug therapy for patients with type 2 diabetes.

描述（由申请人提供）： 药物遗传学领域旨在了解遗传变异如何导致药物疗效或毒性的变异。噻唑烷二酮（TZD）类药物吡格列酮和罗格列酮通常用于治疗2型糖尿病。目前，尚不清楚遗传变异是否会影响人体中TZD的处置（药代动力学）和反应（药效学）。此外，很少有研究评估遗传学是否影响糖尿病临床药理学中抑制性药物相互作用的程度。本申请中拟定的研究将重点关注细胞色素P450 2C8（CYP 2C8）代谢酶基因内的遗传变异。CYP2C8负责TZD的肝脏代谢。该基因内的多态性降低了代谢酶的活性。CYP2C8多态性对人体TZD药代动力学或药效学的影响程度尚未完全阐明。我们将确定CYP2C8基因的遗传多态性是否会导致白人和非裔美国人2型糖尿病患者吡格列酮药代动力学和药效学的变异性。 与药物处置和反应一样，抑制性药物间相互作用引起的药代动力学变化幅度也存在个体间变异性。药物相互作用与糖尿病药物治疗密切相关，因为药物代谢的抑制可能会增强降糖药的疗效或毒性。本申请中的研究将研究吉非罗齐介导的CYP2C8对吡格列酮代谢的抑制作用。我们将确定CYP2C8多态性是否影响吉非罗齐改变吡格列酮在人体内代谢和药代动力学的程度。这样做，我们将针对一个重要的，但定义不明确的领域，糖尿病临床药理学。 这一系列研究的长期目标是更全面地描述遗传学对TZD处置、反应和药物相互作用中个体间变异性的贡献。 糖尿病药物遗传学研究的目标是更好地了解一个人的遗传组成如何影响对糖尿病药物的反应。在未来，这些信息可能被用来帮助选择适当的药物治疗2型糖尿病患者。