Effect of different hemodialysis modalities on hepatic CYP450 metabolism

描述（由申请人提供）：在终末期肾病（ESRD）患者人群中，全国每年发生近22，000起药物不良事件。向ESRD患者给予全剂量的肝代谢药物可能使其处于与给予全剂量的肾消除药物相似的药物毒性风险。每日短时间血液透析（SDHD）是一种新兴的模式，每周6天提供2小时血液透析（HD）疗程。与每周三次HD相比，其更好的尿毒症溶质清除率可能导致CYP 450代谢代谢的改善。这一建议的中心假设是，更大的尿毒症溶质清除率提高肝脏CYP 450代谢活性。这一假设将通过三个目标进行检验。第一个目的是确定通过平衡Kt/V测量的尿素清除率是否与体外CYP 450代谢活性相关。第二个和第三个目标将分别确定SDHD是否具有比每周三次HD更高的肝脏CYP 450代谢活性，体外和体内。对于第一个目标，将在4小时HD治疗期间的特定时间点采集血样。将在这些时间点测定体外肝脏CYP 450 3A 4活性和平衡Kt/V，并分析相关性。对于目的2，将从接受每周三次HD的受试者中采集血样，并用人重组CYP 2C 9、2D 6和3A 4肝微粒体孵育。然后在受试者接受SDHD后重复该实验。对于目标3，将向接受每周3次、4小时HD的受试者给予由肝脏、CYP 450酶CYP 2C 9、2D 6和3A 4的药物探针组成的混合药物。然后抽取血液样本并分析探针代谢物，以确定这些酶的代谢活性。在受试者接受SDHD后重复该实验。然后将比较这两种不同HD模式的体外和体内CYP 450代谢活性。该研究项目将检查和描述ESRD药物的肝脏代谢，重点是间歇性，每周三次和每日短时间血液透析。这项研究对于确保每周接受三次血液透析和日益增长的每日短时间血液透析方式的患者的药物治疗仍然安全有效至关重要。这些研究和指导这些研究的开展也将促进德克尔博士转变为独立资助的研究者。 公共卫生相关性：本项目将确定每日透析的患者是否具有上级毒素清除能力，以及这种上级清除能力是否导致肝酶功能改善。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，每日透析患者如何给药。

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.