Altered Hepatic Disposition of Statins by Diabetes Mellitus

描述(由申请人提供)：药物代谢酶(DME)和转运体介导了一系列化合物的解毒和消除，尽管关于1型或2型糖尿病患者这些机制的调节和活性的数据很少。最近，我们观察到糖尿病患者的阿托伐他汀(ATV)内酯浓度显著升高。此外，在糖尿病供者的肝脏中，我们发现细胞色素P450 3A4(CYP3A4)显著下调，该基因负责所有上市药物中约55%的生物转化。这一观察结果可能在一定程度上解释了我们的临床观察，即糖尿病患者ATV清除量降低。该项目的长期目标是改善糖尿病患者的药物治疗。本提案的目的是在R15赠款机制的背景下，表征糖尿病类型(1型与2型)对DME表达和活性的影响，以及负责ATV处置的运输机制。中心假说是，糖尿病和相关疾病不同地调节DME和转运机制，从而导致包括ATV在内的外源物质的清除改变。这项研究的基本原理是，了解糖尿病对DME或运输机制的影响将有助于临床医生为个别患者的治疗做出更明智的选择。其具体目的是(1)利用1型糖尿病和2型糖尿病及非糖尿病供者的人肝脏，研究糖尿病类型和程度、高血糖和/或脂肪肝对CYP3A4活性和调节的影响；(2)通过使用原代人类肝细胞培养，评估非CYP3A4因素对ATV肝脏处置的贡献；以及(3)通过使用原代人类肝细胞培养，描述与糖尿病相关的不同因素在调节药物代谢酶和转运体方面的相互作用。总的来说，本提案中描述的研究应该提供关于糖尿病对ATV代谢和运输的影响的有用信息。了解糖尿病对ATV处置机制的影响可能有助于设计更安全、更有效的他汀类药物给药方法。 公共卫生相关性：流行病学研究表明，他汀类降胆固醇药对糖尿病患者产生更多副作用。糖尿病很可能 影响几种控制药物处置的机制，包括分解药物分子的酶活性的变化。我们的目的是描述糖尿病对几种负责他汀类药物从人体清除的机制的影响。

DESCRIPTION (provided by applicant): Drug metabolizing enzymes (DMEs) and transporters mediate detoxification and elimination of a wide range of compounds, although minimal data are available on the regulation and activity of these mechanisms in humans with type 1 or type 2 diabetes mellitus. Recently, we have observed significantly higher concentrations of atorvastatin (ATV) lactones in patients with diabetes mellitus. Furthermore, in the livers of diabetic donors, we have shown significant downregulation of cytochrome P450 3A4 (CYP3A4) that is responsible for the biotransformation of approximately 55% of all marketed medications. This observation may explain, in part, our clinical observations of a reduced clearance of ATV in diabetic patients. The broad long-term objective of this project is to improve pharmacotherapy in patients with diabetes mellitus. The objective of the current proposal, in the context of a R15 grant mechanism, is to characterize the effect of diabetes type (type 1 vs. type 2) on the expression and activity of DMEs and transport mechanisms responsible for disposition of ATV. The central hypothesis is that diabetes and associated conditions differentially regulate DMEs and transport mechanisms, thus, resulting in the altered clearance of xenobiotics including ATV. The rationale for this study is that understanding the effect of diabetes on DME or transport mechanisms will assist clinicians to make more-informed choices for the treatment of individual patients. The specific aims are to (1) Characterize the effect of diabetes type and degree of hyperglycemia and/or fatty liver on the CYP3A4 activity and regulation using human livers from type 1 vs. type 2 diabetic and non-diabetic donors (2) Evaluate the contribution of non-CYP3A4 factors on hepatic disposition of ATV and (3) Describe the inter-play between different factors associated with diabetes on the regulation of drug metabolizing enzymes and transporters, by the use of primary human hepatocyte cultures. Collectively, the studies described in this proposal should provide useful information on the effect of diabetes mellitus on ATV metabolism and transport. An understanding of the effects of diabetes on the mechanisms governing ATV disposition may help in devising safer and more efficacious dosing methods for statins in this patient group. PUBLIC HEALTH RELEVANCE: Epidemiological studies suggest that statin cholesterol lowering agents, generate more side effects in patients with diabetes mellitus. Diabetes is likely to influence several mechanisms governing drug disposition, including changes in the activity of enzymes that break down drug molecules. Our aim is to characterize the effects of diabetes on several mechanisms responsible for the clearance of statins from the human body.