Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Urquhart, Brad L.

Abstract

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 CYP2C drug-metabolizing enzymes. Diabetes was induced in male C57BL/6 mice and female hPXR/hCAR/CYP3A4 humanized mice using streptozotocin (STZ). Male STZ-treated mice showed no differences in mRNA levels of Cyp3a11 and Cyp2c29, while female STZ-treated mice had significantly decreased mRNA levels of hCAR and Cyp2e1. Male C57BL/6 mice had no differences in Cyp3a11 enzymatic activity, while female hPXR/hCAR/CYP3A4 STZ-treated mice had an increased CYP3A4 enzymatic activity. Small changes in CYP expression and activity in diabetes and DN may lead to altered drug pharmacokinetics. This study highlights the importance of understanding changes in drug disposition to reduce clinically significant adverse drug reactions.

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