Effect of different hemodialysis modalities on hepatic CYP450 metabolism

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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.