Characterization of the effect of chronic kidney disease on hepatic reduction: In-vitro and in-vivo studies of warfarin

Chronic kidney disease (CKD) affects the disposition of drugs by altering their renal excretion. Well-established evidence suggests that CKD also impacts the nonrenal clearance of drugs by modulating drug metabolism and transport. The overall objective of this dissertation was to investigate the effect of CKD on hepatic reduction, an important Phase I drug metabolism pathway. In order to achieve our goals, a novel analytical method was developed and validated to measure warfarin and its alcohol metabolites.;In vitro studies utilizing rat hepatic cytosol and microsomes showed significant decreases in the formation of RS/SR-warfarin alcohol in the CKD group compared to control, suggesting decreased reductase activity. Significantly decreased mRNA and protein expression (>30%) of selective reductase enzymes was also observed in rats with CKD. In vitro studies of human liver cytosol and microsomes collected from patients with end stage renal disease (ESRD) revealed a trend toward decreased formation of RS/SR-warfarin alcohol. A significant decrease (65%) in protein expression of carbonyl reductase 1 was observed in livers from ESRD compared to control livers. Together, the in vitro findings implicate transcriptionally or translationally mediated changes in reductase enzyme function in CKD.;In vivo studies assessing the effect of CKD on steady-state warfarin and warfarin alcohol disposition showed increased concentrations of RR/SS-warfarin alcohol along with decreased kidney function, indicating impaired renal elimination of the RR/SS-warfarin alcohol metabolite in kidney disease patients. Additionally, increased free and total S/R warfarin observed in ESRD patients potentially suggests reduced CYP2C9 activity.;Collectively, our findings demonstrate that drug reduction is impacted by kidney function, and provide a mechanism for altered nonrenal clearance and disposition of drugs in CKD. The findings of these studies may be clinically relevant in improving the management of drug substrates of reductases, specifically warfarin, in patients with CKD. Given the high frequency with which these drugs are prescribed for CKD patients, dosing adjustments and frequent monitoring may be warranted.