Genetic predictors of thiazolidinedione response

描述(由申请人提供)： 药物遗传学领域的目的是了解遗传变异如何影响药物疗效或毒性的可变性。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TZD在人类中的处置(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药物-药物相互作用的大小。在这项申请中提出的研究将集中在细胞色素P450 2C8(细胞色素P450 2C8)代谢酶基因内的遗传变异。CYP2C8负责TZD的肝脏代谢。该基因内的多态会降低代谢酶的活性。CYP2C8基因多态对TZD在人体内的药代动力学或药效学的影响程度尚未完全阐明。我们将确定在高加索人和非裔美国人的2型糖尿病患者中，CYP2C8基因的遗传多态是否会导致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，药物-药物相互作用抑制引起的药代动力学变化的大小也存在个体间的差异。药物相互作用与糖尿病药物治疗密切相关，因为抑制药物代谢可能会增强降糖剂的疗效或毒性。本应用中的研究将探讨吉非罗齐介导的CYP2C8对吡格列酮代谢的抑制作用。我们将确定CYP2C8基因多态性是否会影响吉非罗齐改变人体吡格列酮代谢和药代动力学的程度。在这样做的过程中，我们将瞄准糖尿病临床药理学的一个重要但定义不明确的领域。 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的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基因构成如何影响对糖尿病药物的反应。未来，这一信息可能有助于为2型糖尿病患者选择合适的药物治疗。

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.