Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease

ABSTRACT

Introduction: The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications.

Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD.

Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.

KEYWORDS:

• Non-alcoholic fatty liver disease
• drug treatment
• drug metabolism
• drug transport
• adverse events

Article highlights

• NAFLD is associated with obesity and other cardiovascular risk factors so that patients with NAFLD often require drug treatment.

• Activity of important metabolism enzymes in the liver such as CYP3A4 and several UGT isoforms is reduced hindering activation or detoxification of many drugs in clinically relevant amounts.

• Downregulation of basolateral uptake and biliary efflux transporters impedes drug metabolism, while upregulation of basolateral efflux transporters provides the ability of sinusoidal re-secretion, resulting in higher systemic retention.

• Hepatic fibrosis and steatosis may contribute to reduced uptake and distribution of drugs in the liver, thereby amplifying effects of changed metabolism and transport.

• NAFLD-related alterations in metabolism may be more pronounced in carriers of genetic variants predisposing to adverse effects of common medical drugs.

• Until now only non-serious adverse events have been described in NASH patients, so that most drug treatments seem to be safe in the recommended doses. However, systematic clinical studies in this patient group are lacking and should be obtained in the near future.

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Acknowledgment

The authors would like to thank Dr. Noelle Polakos for critical reading of the manuscript and language editing.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

No funding was received for the preparation of this manuscript.