The impact of progressive chronic kidney disease on hepatic drug metabolism.

Abstract

Nonrenal clearance pathways such as drug metabolism are decreased in severe chronic kidney disease (CKD). The impact of progression of CKD on hepatic drug metabolism is unknown. We characterized the effect of progressive CKD on hepatic cytochrome P450 expression and evaluated dysbiosis and uremia as kidney function declined. Rats fed control or CKD-inducing adenine diet were studied at 5 time points over 42 days. Cytochrome P450 expression and activity were compared with alterations in the (1) plasma and liver metabolome and (2) gut bacterial microbiota. CYP3A2 and CYP2C11 were downregulated in CKD by ≥76% (P < .001) concurrently with or slightly prior to CKD onset as defined by serum creatinine. Metabolite profiles were altered prior to changes in the gut microbiota, and gut-derived uremic toxins including indoxyl sulfate, phenyl sulfate, and 4-ethylphenyl sulfate correlated with CYP3A2 or CYP2C11 expression. Bacterial genera Turicibacter and Parabacteroides were identified as being characteristic of CKD. In conclusion, CYP3A2 and CYP2C11 are downregulated before dysbiosis and uremia. SIGNIFICANCE STATEMENT: This study describes the effect of progressive kidney disease on hepatic CYP2C11 and CYP3A2 enzyme expression and activity in a rat model of CKD. Expression and activity of drug metabolizing enzymes occurs prior to uremia or dysbiosis.