Effect of different hemodialysis modalities on hepatic CYP450 metabolism

描述（由申请人提供）：全国每年在终末期肾病（ESRD）患者人群中发生近22,000例药物不良事件。对ESRD患者给予全剂量肝脏代谢药物可能使他们面临与给予全剂量肾脏消除药物相似的药物毒性风险。短日血液透析（SDHD）是一种新兴的方式，提供两小时的血液透析（HD）疗程，每周6天。它比每周三次的HD更好的尿毒症溶质清除可能导致CYP450代谢代谢的改善。该建议的中心假设是，更大的尿毒症溶质清除改善肝脏CYP450代谢活性。这一假设将由三个目标来检验。第一个目的是确定平衡Kt/V测量的尿素清除率是否与体外CYP450代谢活性相关。第二个和第三个目标将分别确定SDHD在体外和体内是否比每周三次的HD具有更高的肝脏CYP450代谢活性。第一个目标是在四小时的高清课程中，在特定的时间点抽取血液样本。在体外，将在这些时间点测定肝脏CYP450 3A4活性和平衡Kt/V，并分析相关性。对于Aim 2，将从每周接受三次HD治疗的受试者中抽取血液样本，并与人、重组CYP2C9、2D6和3A4肝微粒体孵育。该实验将在受试者接受sdd治疗后重复进行。对于Aim 3，将给接受每周一次、4小时HD治疗的受试者使用鸡尾酒药物，包括肝脏药物探针、CYP450酶CYP2C9、2D6和3A4。然后将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。本实验将在受试者接受sdd治疗后重复进行。然后比较这两种不同HD模式的体内和体外CYP450代谢活性。本研究项目将研究并描述ESRD中药物的肝脏代谢，重点是间歇性、每周三次和每天短时间的血液透析。这项研究对于确保每周接受三次血液透析和日益增加的每日短时间血液透析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进行也将促进德克尔博士过渡到一个独立资助的研究者。

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.