Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr. Brad Urquhart

Abstract

Chronic kidney disease (CKD) occurs as a result of declining renal function for 3 or more months. CKD effects 1 in 10 Canadians and is associated with a number of co-morbidities including diabetes and cardiovascular disease. To manage CKD and associated co-morbidities, patients take an average of 12 medications with a median pill burden of 19. Indeed, renal drug elimination is compromised in CKD, as declining glomerular filtration reduces drug excretion into urine. More recently, studies have provided evidence of altered non-renal drug clearance in CKD. The majority of drug clearance occurs in the liver by CYP2C and CYP3A drug metabolizing enzymes. Hepatic CYP2C and CYP3A drug metabolizing enzymes are tightly regulated by nuclear receptors. The majority of CKD patients have mild to moderate degrees of CKD and the potential for altered hepatic drug metabolism at these earlier stages is unknown. As renal function declines, patients begin to experience the uremic condition, which consists of metabolic waste product accumulation in the blood. A number of studies suggest that these uremic toxins may mediate the downregulation of hepatic CYP2C and CYP3A; however, the mechanism by which this occurs remains to be determined. My overall hypothesis is that hepatic drug metabolism is altered in CKD.

Herein, we evaluate the effects of moderate CKD on hepatic drug metabolism and determine a possible mechanism of CYP2C and CYP3A downregulation in rats with CKD. In a rat model of moderate CKD, hepatic CYP2C and CYP3A function and expression were significantly decreased demonstrating a negative exponential correlation with kidney function. Transcriptional activation in both the CYP2C and CYP3A promoters was reduced as a result of decreased nuclear receptor binding and histone acetylation. Untargeted metabolomics was utilized to identify potential uremic mediators of hepatic CYP2C and CYP3A altered expression and function. Gut-derived uremic toxins accounted for the most significant metabolic signatures defining plasma and liver tissue in CKD, leading to the evaluation of these toxin effects on hepatic CYP2C and CYP3A. Reduction of gut-derived uremic toxins did not recover CYP2C and CYP3A function and expression in CKD. In conclusion, these studies further our understanding of hepatic drug metabolizing enzyme downregulation in the setting of CKD.


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