Effect of changes in metabolic enzymes and transporters on drug metabolism in the context of liver disease: Impact on pharmacokinetics and drug–drug interactions
Sara Armani, Andreas Geier, Thomas Först, Uta Merle, David Alpers, Martin W. Lunnon
Abstract
Changes in the pharmacokinetic and resulting pharmacodynamic properties of drugs are common in many chronic liver diseases, leading to adverse effects, drug interactions and increased risk of over- or underdosing of medications. Structural and functional hepatic impairment can have major effects on drug metabolism and transport. This review summarizes research on the functional changes in phase I and II metabolic enzymes and in transport proteins in patients with metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis and cirrhosis, providing a clinical perspective on how these changes affect drug uptake and metabolism. Generally, a decrease in expression and/or activity of many enzymes of the cytochrome P450 family (e.g. CYP2E1 and CYP3A4), and of influx and efflux transporters (e.g. organic anion-transporting polypeptide [OATP]1B1, OATP2B1, OAT2 and bile salt export pump), has been recently documented in patients with liver disease. Decreased enzyme levels often correlate with increased severity of chronic liver disease. In subjects with hepatic impairment, there is potential for strong alterations of drug pharmacokinetics due to reduced absorption, increased volume of distribution, metabolism and extraction. Due to the altered pharmacokinetics, specific drug-drug interactions are also a potential issue to consider in patients with liver disease. Given the huge burden of liver disease in western societies, there is a need to improve awareness among all healthcare professionals and patients with liver disease to ensure appropriate drug prescriptions.