The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease. The whole concept of NAFLD has now moved into metabolic dysfunction-associated fatty liver disease (MAFLD) to emphasize the strong metabolic derangement as the basis of the disease. Several studies have suggested that hepatic gene expression was altered in NAFLD and NAFLD-related metabolic comorbidities, particularly mRNA and protein expression of phase I and II drug metabolism enzymes (DMEs). NAFLD may affect the pharmacokinetic parameters. However, there were a limited number of pharmacokinetic studies on NAFLD at present. Determining the pharmacokinetic variation in patients with NAFLD remains challenging. Common modalities for modeling NAFLD included: dietary induction, chemical induction, or genetic models. The altered expression of DMEs has been found in rodent and human samples with NAFLD and NAFLD-related metabolic comorbidities. We summarized the pharmacokinetic changes of clozapine (CYP1A2 substrate), caffeine (CYP1A2 substrate), omeprazole (Cyp2c29/CYP2C19 substrate), chlorzoxazone (CYP2E1 substrate), midazolam (Cyp3a11/CYP3A4 substrate) in NAFLD. These results led us to wonder whether current drug dosage recommendations may need to be reevaluated. More objective and rigorous studies are required to confirm these pharmacokinetic changes. We have also summarized the substrates of the DMEs aforementioned. In conclusion, DMEs play an important role in the metabolism of drugs. We hope that future investigations should focus on the effect and alteration of DMEs and pharmacokinetic parameters in this special patient population with NAFLD.