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Hepatic Drug Metabolism, Uremic Toxins And Bacterial Composition Over Chronic Kidney Disease Progression, Emily Dee Hartjes

Electronic Thesis and Dissertation Repository

Uremic toxin retention and an altered gut microbiota are suspected to influence cytochrome P450s (CYPs) contributing to the unpredictable pharmacokinetics in chronic kidney disease (CKD). We aim to characterize dysbiosis and uremia to elucidate associations between CYP expression and CKD progression. Rats fed control or CKD-inducing diet were subsequently sacrificed across five time points over 42 days. CYP expression and activity were compared to alterations in the 1) plasma and liver metabolome and 2) bacterial microbiota. CYP3A2 and CYP2C11, respectively, were downregulated in CKD by ≥76% (p<0.001) simultaneously or slightly premature to CKD onset defined by creatinine. Metabolite profiles were altered before the gut microbiota and gut-derived uremic toxins including indoxyl sulfate, phenyl sulfate and 4-ethylphenyl sulfate correlated with CYP3A2 or CYP2C11. Identified bacterial genera, Turicibacter and Parabacteroides, characterized CKD and require future study. In conclusion, CYP3A2 and CYP2C11 are downregulated prior to dysbiosis but correlate with select uremic toxins.