Altered Hepatic Disposition of Statins by Diabetes Mellitus

描述（由申请人提供）：药物代谢酶（DME）和转运蛋白介导多种化合物的解毒和消除，尽管关于1型或2型糖尿病患者中这些机制的调节和活性的数据很少。 最近，我们已经观察到显着较高浓度的阿托伐他汀（ATV）内酯的糖尿病患者。 此外，在糖尿病供体的肝脏中，我们发现细胞色素P450 3A 4（CYP 3A 4）显著下调，这是所有上市药物约55%生物转化的原因。 这一观察结果可以部分解释我们在糖尿病患者中ATV清除率降低的临床观察结果。 该项目的广泛长期目标是改善糖尿病患者的药物治疗。 在R15补助机制的背景下，当前提案的目的是表征糖尿病类型（1型与2型）对DME的表达和活性以及负责ATV处置的运输机制的影响。 核心假设是糖尿病和相关病症差异性地调节DME和转运机制，从而导致包括ATV在内的外源性物质的清除改变。 这项研究的基本原理是，了解糖尿病对DME或转运机制的影响将有助于临床医生为个体患者的治疗做出更明智的选择。 具体目的是（1）使用来自1型与2型糖尿病和非糖尿病供体的人肝脏表征糖尿病类型和高血糖和/或脂肪肝程度对CYP 3A 4活性和调节的影响（2）评价非CYP 3A 4因素对ATV肝脏处置的贡献和（3）描述非CYP 3A 4因素对ATV肝脏处置的影响。通过使用原代人肝细胞培养物，研究与糖尿病相关的不同因素对药物代谢酶和转运蛋白的调节作用。 总的来说，本提案中描述的研究应提供有关糖尿病对ATV代谢和运输影响的有用信息。 了解糖尿病对ATV处置机制的影响可能有助于设计更安全和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，他汀类降胆固醇药物在糖尿病患者中产生更多的副作用。 糖尿病很可能 影响药物处置的几种机制，包括分解药物分子的酶活性的变化。 我们的目的是表征糖尿病对负责从人体清除他汀类药物的几种机制的影响。

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.