Effect of Chronic Kidney Disease on Hepatic Clearance of Drugs in Rats

Abstract

The pharmacokinetics of some hepatically cleared drugs have been reported to fluctuate in patients with renal impairment, but the definitive factors have not been clarified. We compared the pharmacokinetics of some drugs with different hepatic elimination processes in a chronic kidney disease (CKD) rat model, to optimize their administration during kidney injury. We chose indocyanine green (ICG), midazolam (MDZ), and acetaminophen (APAP) as reference drugs to determine changes in hepatic clearance pathways in presence of CKD. Drugs were intravenously administered via the jugular vein to the CKD model rats, previously established by adenine administration, and then, blood, bile, and urine samples were collected. The plasma concentration of ICG, which is eliminated into the bile without biotransformation, increased; and its total body clearance (CL tot) significantly decreased in the CKD group compared to the control group. Moreover, the plasma concentrations of MDZ and APAP, metabolized in the liver by CYP3A and Ugt1a6 enzymes, respectively, were higher in the CKD group than in the control group. The biliary clearances of APAP and its derivative APAP-glucuronide increased in the CKD group, whereas their renal clearances were markedly decreased with respect to those in the control group. Altogether, plasma concentrations of some hepatically eliminated drugs increased in the CKD rat model, but depending on their pharmacokinetic characteristics. This study provides useful information for optimizing the administration of some hepatically cleared drugs in CKD patients.

Paradoxical reduction of plasma lipids and atherosclerosis in mice with adenine-induced chronic kidney disease and hypercholesterolemia

“…We observed that mice either co-treated or pre-treated with adenine neither exhibited histologic evidence of liver damage nor elevated ALT levels, suggesting that adenine was not toxic to the liver. Our results support findings from other studies showing a lack of adenine hepatotoxicity ( 42 , 43 ). However, another study reported a hepatotoxic effect of adenine as demonstrated by elevated liver enzymes in response to inflammation ( 44 ).…”

Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites

“…We observed significantly higher concentrations of paracetamol and glucuronide conjugate in patients with renal dysfunction. Renal dysfunction has been observed to result in reduced hepatic clearance by an extent of around 30% [25]. Sulfation pathway has been shown to be saturable at therapeutic doses and so sulphate conjugates have been debated to play a limited role in hepatotoxicity [26].…”