Non-Renal Alterations of Drug Disposition in Chronic Kidney Disease
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.