Effect of different hemodialysis modalities on hepatic CYP450 metabolism

描述(申请人提供)：在全国范围内，终末期肾病(ESRD)患者群体中每年发生近22,000起药物不良事件。给ESRD患者全量服用肝脏代谢药物可能会使他们面临与全量肾脏消除药物类似的药物毒性风险。短日血液透析(SDHD)是一种新兴的方式，提供每周6天两小时的血液透析(HD)。它的尿毒症溶质清除率可能比每周三次的HD更好，可能会改善细胞色素P450的代谢。这一建议的中心假设是，尿毒症溶质清除量越大，肝脏细胞色素P450的代谢活性越高。这一假设将通过三个目标进行检验。第一个目标将确定平衡Kt/V测量的尿素清除量是否与体外细胞色素P450代谢活性相关。第二个和第三个目标将分别在体外和体内确定SDHD是否比每周三次的HD具有更高的肝脏细胞色素P450代谢活性。对于第一个目标，血液样本将在四个小时的HD过程中的特定时间点采集。体外测定各时间点肝脏细胞色素P450 3A4活性和平衡Kt/V，并进行相关性分析。对于目标2，血液样本将从接受每周三次HD的受试者中提取，并与人、重组CYP2C9、2D6和3A4肝微体孵育。在受试者接受SDHD后，这个实验将重复进行。对于Aim 3，将给接受每周三次、4小时HD的受试者注射一种药物鸡尾酒，其中包括肝脏的药物探针、CYP450酶CYP2C9、2D6和3A4。血液样本将被提取并分析以检测代谢物，以确定这些酶的代谢活性。这个实验将在受试者接受SDHD后重复进行。然后将比较这两种不同HD模式的体外和体内CYP450代谢活性。这项研究项目将检查和表征ESRD患者药物的肝脏代谢，重点是间歇性、每周三次和每日短期血液透析。这项研究对于确保每周三次的药物治疗和日益增长的短日血液透析方式的药物治疗仍然安全有效至关重要。这些研究和对这些研究的指导也将有助于德克尔博士向独立资助的研究人员过渡。 公共卫生相关性：该项目将确定每天透析的患者是否有更好的毒素清除能力，以及这种优势清除是否会改善肝酶功能。这反过来又改变了药物从体内清除的方式。最终，我们的目标是更好地了解与传统的每周三次透析相比，如何在每日透析患者中给药。

DESCRIPTION (provided by applicant): Nationwide nearly 22,000 adverse drug events occur annually in the end-stage renal disease (ESRD) patient population. Administering the full dose of a hepatically metabolized medication to an ESRD patient may place them at similar risk for drug toxicity as administering a full dose of a renally-eliminated medication. Short-daily hemodialysis (SDHD) is an emerging modality that provides two-hour hemodialysis (HD) sessions, 6 days a week. Its putatively better uremic solute clearance than thrice-weekly HD may result in improved CYP450 metabolic metabolism. The central hypothesis of this proposal is that greater uremic solute clearance improves hepatic CYP450 metabolic activity. This hypothesis will be tested by three aims. The first aim will determine if urea clearance as measured by equilibrated Kt/V correlates with in-vitro CYP450 metabolic activity. The second and third aim will determine if SDHD has higher hepatic CYP450 metabolic activity than thrice-weekly HD, in-vitro and in-vivo, respectively. For the first aim, blood samples will be drawn at specific time points during a four-hour HD session. In-vitro, hepatic CYP450 3A4 activity and equilibrated Kt/V will be determined at these time points and analyzed for correlation. For Aim 2, blood samples will be drawn from subjects receiving thrice-weekly HD and incubated with human, recombinant CYP2C9, 2D6 and 3A4 hepatic microsomes. This experiment will then be repeated after the subjects are receiving SDHD. For Aim 3, a drug cocktail consisting of medication probes for the hepatic, CYP450 enzymes CYP2C9, 2D6 and 3A4 will be administered to subjects receiving thrice-weekly, 4 hour HD. Blood samples will then be drawn and analyzed for probe metabolites to determine the metabolic activity of these enzymes. This experiment will be repeated after the subjects are receiving SDHD. The in-vitro and in-vivo CYP450 metabolic activity of these two different HD modalities will then be compared. This research project will examine and characterize the hepatic metabolism of medications in ESRD with a focus on intermittent, thrice weekly and short-daily hemodialysis. This research is crucial to ensure that the pharmacotherapy for patients receiving thrice-weekly and the growing short-daily hemodialysis modality remains safe and effective. These studies and mentoring of the conduct of these studies will also facilitate Dr. Decker's transition to an independently funded investigator. PUBLIC HEALTH RELEVANCE: This project will determine if patients with daily dialysis have superior removal of toxins and if this superior removal leads to improved liver enzyme function. This, in turn alters the way that drugs are cleared from the body. Ultimately, the goal is to better understand how to dose drugs in patients on daily dialysis compared to the traditional thrice weekly dialysis.