Drug disposition alterations in liver disease: extrahepatic effects in cholestasis and nonalcoholic steatohepatitis

Abstract

Introduction: The pharmacokinetics (PK) of drugs and xenobiotics, namely pharmaceuticals, is influenced by a host of factors that include genetics, physiological factors and environmental stressors. The importance of disease on the disposition of xenobiotics has been increasingly recognized among medical professionals for alterations in key enzymes and membrane transporters that influence drug disposition and contribute to the development of adverse drug reactions.

Areas covered: This review will survey pertinent literature of how liver disease alters the PKs of drugs and other xenobiotics. The focus will be on nonalcoholic steatohepatitis as well as cholestatic liver diseases. A review of basic pharmacokinetic principles, with a special emphasis on xenobiotic metabolizing enzymes and membrane transporters, will be provided. Specifically, examples of how genetic alterations affect metabolism and excretion, respectively, will be highlighted. Lastly, the idea of 'extrahepatic' regulation will be explored, citing examples of how disease manifestation in the liver may affect drug disposition in distal sites, such as the kidney.

Expert opinion: An expert opinion will be provided highlighting the definite need for data in understanding extrahepatic regulation of membrane transporters in the presence of liver disease and its potential to dramatically alter the PK and toxicokinetic profile of numerous drugs and xenobiotics.

Keywords: adverse drug reactions; cytochrome P450; liver disease; membrane transporters; pharmacokinetics.