Erythropoietin and Chronic Kidney Disease Alter Hepatic Expression of Cytochrome P450 Enzymes and Drug Transport Proteins

Chronic kidney disease (CKD) is a progressive disease involving the irreversible loss of kidney function. Patients with CKD require concurrent dosing of many medications to manage their disease and associated comorbidities. Pharmacokinetic studies using patients with CKD and previous studies using animal models of CKD have demonstrated changes in hepatic drug metabolism and transport. Our studies aim to examine the effects that end-stage renal disease (ESRD) and continuous dosing of recombinant human erythropoietin (EPO) have on hepatic cytochrome P450 (P450) drug metabolizing enzymes and drug transport proteins. We used an adenine-fed rat model of CKD to demonstrate that EPO decreases expression and function of hepatic CYP3A2. Additionally, P450 and drug transport protein expression were evaluated in cadaveric liver samples from ESRD patients. Human ESRD liver samples displayed significantly different mRNA expression hepatic transport proteins OATP1B1, OATP1B3, breast cancer resistance protein and P-glycoprotein, relative to control liver samples (p \u3c 0.05). Our results suggest that, in the human CKD patient, changes in drug disposition are likely a result of changes in hepatic drug transport protein expression