Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Urquhart, Brad L.

2nd Supervisor

Weir, Matthew

Co-Supervisor

Abstract

Chronic kidney disease (CKD) results in profound changes to non-renal drug elimination pathways including hepatic drug metabolism and hepatic transport mediated excretion. This results in complex pharmacological changes to drug disposition in the setting of kidney dysfunction. Four million Canadians are affected by CKD and the average CKD patient takes 14 medications daily with up to 40% experiencing adverse drug reactions at some point in their disease progression. Better elucidation of these changes in the setting of CKD is required to properly dose medications to provide therapeutic benefits while minimizing toxicity. This thesis aimed to better understand the impact kidney dysfunction has on drug metabolism by cytochrome P450s, transport mediated excretion by organic anion polypeptides (OATPs), and drug-drug interactions (DDIs). Various methods of studying drug disposition were utilized such as ex vivo metabolism assays of cannabinoids in rat liver microsomes, in vivo drug disposition studies of fexofenadine in humanized mice, clinical studies utilizing single timepoint blood sampling, as well as a population-based retrospective cohort study to investigate DDIs in the setting of CKD. It was found that cannabinoid metabolism is altered in a rat model of CKD and results in unique metabolite profiles compared to healthy rats. Mice humanized for hepatic OATP1B1/1B3 did not result in the same phenotype observed in clinical studies of increased exposure to fexofenadine in CKD patients. However, the use of single timepoint measurements of fexofenadine to estimate overall exposure was proven useful. This single timepoint method will aid in the design of future clinical investigations into pharmacological changes of fexofenadine in CKD. Additionally, health administrative databases were utilized through the Institute for Clinical Evaluative Sciences (ICES) to uncover an increased relative risk of hyperkalemia and acute kidney injury for patients co-prescribed an angiotensin receptor blocker (ARBs) with clarithromycin compared to azithromycin. Additionally, the DDI between ARBs and clarithromycin was found to be influenced by baseline kidney function assessed by estimated glomerular filtration rate (eGFR). Overall, these projects evaluate various pharmacological processes in the setting of CKD and allow for further understanding of the complex pharmacological phenomenon in this population.

Summary for Lay Audience

Pharmacology is the study of how biology interacts with medications – including what the body does to the drug and what the drug does to the body. There are many pharmacological processes that influence how people respond to medications, which can include the breakdown (metabolism) of drugs and removal of drugs in the urine or feces. In various disease states, such as liver or kidney dysfunction, these pharmacological processes can become altered and influence the way someone responds to a drug. For example, reduced elimination of a drug in the urine can increase how long that medication remains in the body potentially leading to toxic effects. Similarly, when drug metabolism in the liver is impaired, drugs can accumulate in the body. When patients are affected by long term kidney dysfunction, or chronic kidney disease (CKD), they are at an increased risk of toxic side effects from medications. Interestingly, the production of urine is not the only process impacted in CKD as liver function has also been shown to be impaired as a result of reduced kidney function. This creates a complex pharmacological environment and the reasons to why kidney function impairs drug elimination by the liver is not completely understood. These current projects applied various experimental methods to gain a better understanding of why CKD impacts drug response. Utilization of unique techniques such as metabolism experiments, animal models, clinical studies, and health administrative database research provided a wide range of perspectives into pharmacology in CKD. Metabolism of the active components of cannabis was shown to be impaired in CKD rats. It was shown that a single blood sample of the antihistamine, fexofenadine, could be used as a measure of total drug exposure, eliminating the need for multiple blood draws in clinical studies. Additionally, health database analysis revealed a drug interaction between commonly used blood pressure medications and an antibiotic which was also influenced by kidney function. Overall, use of multiple techniques allowed for unique perspectives into various pharmacological processes in the setting of kidney dysfunction.

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