Mechanistic basis of increased susceptibility to nephrotoxicants in chronic liver disease

Abstract

The global prevalence of chronic liver disease (CLD) is a major public health concern due to its ability to alter the predicted pharmacokinetics of xenobiotics, which may lead to nephrotoxicity. CLD etiologies include nonalcoholic steatohepatitis (NASH), alcohol-associated liver disease (ALD), and viral hepatitis, which cause a disruption in drug disposition and elimination through hepatic dysfunction, including expression changes in drug metabolizing enzymes and transporters. While altered drug metabolizing enzymes are of critical consideration for xenobiotic disposition in CLD patients, this review will focus on membrane transporters. This altered disposition may lead to an increase in plasma retention, a decrease in biliary excretion, and result in an increase in systemic exposure to nephrotoxic compounds. Additionally, CLD can elicit changes in renal physiology, such as decreased glomerular filtration rate, further influencing the elimination mechanism of xenobiotics. Investigating the variations in pharmacokinetic profiles of nephrotoxicants because of alterations in hepatic and renal elimination processes in CLD patients is critical for the prevention of adverse drug reactions and improvement of patient outcomes.