Pharmacology, Toxicology and Environmental Health Commons^™

Non-Renal Alterations Of Drug Disposition In Chronic Kidney Disease, Nicholas Tonial

Electronic Thesis and Dissertation Repository

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 …

Expression Of Hepatic Cytochrome P450 Drug Metabolizing Enzymes In Diabetes And Diabetic Nephropathy, Cheng Jay Fang

Electronic Thesis and Dissertation Repository

The prevalence of diabetes worldwide is rapidly increasing. Polypharmacy, along with a high risk of adverse drug reactions, is common in diabetic patients. Cytochrome P450 (CYP) 3A and 2C drug metabolizing enzymes are reduced in chronic kidney disease (CKD), altering drug pharmacokinetics and contributing to adverse drug reactions. A large fraction of commonly prescribed drugs are metabolized by CYP3A and CYP2C. Approximately 40% of all CKD cases are attributed to diabetic nephropathy (DN) and early DN presents as mild kidney disease. This study aims to evaluate the impact of diabetes and DN on levels and activity of hepatic CYP3A and …

Beta Blocker Dialyzability And Effectiveness In Chronic Hemodialysis Patients, Alvin Tieu

Electronic Thesis and Dissertation Repository

Of the minimal information describing drug dialyzability, the majority was obtained prior to modern hemodialysis membranes. This study characterized the dialyzability of the most commonly prescribed beta blockers in patients undergoing high-flux hemodialysis. Eight subjects were recruited to a pharmacokinetic, 4-way crossover trial. Drug concentrations were measured using mass spectrometry and dialyzability determined by the arterial-venous difference and recovery clearance methods. A provincial-wide retrospective cohort study was designed to determine the effect of dialyzability on adverse clinical outcomes. Beta blocker efficacy can be hindered if substantial clearance occurs during dialysis. Our results demonstrate atenolol and metoprolol are extensively cleared during …

Regulation Of Hepatic Drug Metabolizing Enzymes In Chronic Kidney Disease, Thomas J. Velenosi

Electronic Thesis and Dissertation Repository

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 …

N-Acetylcysteine As A Chemoprotectant Against Ifosfamide Nephrotoxicity; From Mechanism To Prevention, Lauren Hanly

Electronic Thesis and Dissertation Repository

The chemotherapy drug ifosfamide is used in the treatment of several childhood cancers. While effective, its use in children results in a 30% incidence of nephrotoxicity, and 5% incidence of Fanconi syndrome. This late effect is caused by oxidative damage, generated by chloroacetaldehyde, a toxic metabolite of ifosfamide cytochrome P450-mediated bioactivation in the kidney tubules. N-acetylcysteine has been identified as a promising strategy to mitigate nephrotoxicity through its antioxidant and glutathione stimulating properties. Furthermore, with current use in children for acetaminophen poisoning, its clinical utility is evident. Both cell and animal models have demonstrated n-acetylcysteine’s effectiveness in mitigating ifosfamide kidney …

Pharmacokinetics And Therapeutic Uses Of Mesna, Murray J. Cutler

Electronic Thesis and Dissertation Repository

In the early 1980s, significant advancement in the safety of ifosfamide therapy was achieved by co-administrating mesna (sodium 2-mercaptoethane sulfonate) to prevent dose-limiting hemorrhagic cystitis. Mesna exerts its protective effect within the urine, where its free sulfhydryl group is able to conjugate cytotoxic metabolites. Within the circulation, however, mesna exists primarily as its inactive disulfide, dimesna. Dimesna is currently undergoing clinical development as a prodrug (BNP7787) to treat cisplatin-induced nephrotoxicity. Remarkably, chemoprotection is achieved without attenuation of efficacy of co-administered anti-cancer agents. This is widely attributed to the kidney-specific disposition and stability of dimesna.

We sought to evaluate the role …