Nonalcoholic Steatohepatitis Alters Phase I Drug Metabolism

Abstract

Variable drug responses (VDRs) are dependent on inter-individual variability in the activity of drug-metabolizing enzymes. As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis (NASH) has been identified as a source of significant inter-individual variation in hepatic drug metabolism. A previous ex vivo study demonstrated significant changes in hepatic CYP activity in adult human NASH. To evaluate the current model in reflecting the hepatic CYP alterations in humans with NASH, the expression profile and the in vivo activities of multiple CYP isoforms were assessed in the prominent diabetic NASH mouse models. Although significant alterations in the profile of CYP expression and function were shown in the diabetic NASH mouse model, a comparison revealed that this model only partially recapitulates the human ex vivo CYP alteration pattern. Therefore, in vivo determination of the effects of NASH on CYP activity should be conducted in human, and more appropriate models are required for future drug metabolism studies in NASH. Compared to adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The following study determined the impact of fatty liver disease severity on the activity of a variety of CYPs in adolescents using the in vivo approach established in the first study. The CYP2C19 enzymatic activity is decreased by 60% in NASH adolescents. A comparison between the in vivo pediatric studies and a previous ex vivo study in adult indicates distinct differences in the activities of CYP1A2 and CYP2C9, which demonstrate that pediatric NASH presents an altered pattern of CYP activity and NASH should be considered as a confounder of drug metabolism for certain CYPs. Furthermore, hepatic alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play critical roles in alcohol metabolism and other cellular metabolism processes, as well as the metabolism of clinical drugs. The alterations in alcohol metabolism processes in response to human NASH progression were investigated using human liver samples. ADH and ALDH expression and function are significantly altered in the progression of NASH, which may have a notable impact on ADH and ALDH associated cellular metabolism processes and lead to significant alterations in drug metabolism mediated by these enzymes. Overall, the major phase I drug metabolizing enzymes are profoundly altered in the progression of human NASH, which may significantly increase the incidence of VDRs. Therefore, the disease state of NASH should be taken into consideration in dosage recommendations and appropriate dose adjustment. Future studies will be needed to translate these findings to guide actual clinical practice.