Regulation of drug-metabolizing enzymes by local and systemic liver injuries

ABSTRACT

Introduction: Drug metabolism and disposition are critical in maintaining the chemical and functional homeostasis of xenobiotics/drugs and endobiotics. The liver plays an essential role in drug metabolism and disposition due to its abundant expression of drug-metabolizing enzymes (DMEs) and transporters. There is growing evidence to suggest that many hepatic and systemic diseases can affect drug metabolism and disposition by regulating the expression and/or activity of DMEs and transporters in the liver.

Areas covered: This review focuses on the recent progress on the regulation of DMEs by local and systemic liver injuries. Liver ischemia and reperfusion (I/R) and sepsis are used as examples of local and systemic injury, respectively. The reciprocal effect of the expression and activity of DMEs on animals’ sensitivity to local and systemic liver injuries is also discussed.

Expert opinion: Local and systemic liver injuries have a major effect on the expression and activity of DMEs in the liver. Understanding the disease effect on DMEs is clinically important due to the concern of disease-drug interactions. Future studies are necessary to understand the mechanism by which liver injury regulates DMEs. Human studies are also urgently needed in order to determine whether the results in animals can be replicated in human patients.

KEYWORDS:

• Animal models
• drug-metabolizing enzyme
• ischemia and reperfusion
• sepsis

Article highlights

• Liver is an essential organ for drug metabolism and disposition.

• Drug metabolism and disposition are facilitated by drug-metabolizing enzymes (DMEs) and transporters, which are highly enriched in the liver.

• Hepatic and systemic diseases can potentially affect drug metabolism and disposition by regulating the expression and/or activity of DMEs and transporters in the liver.

• Understanding the disease effect on DMEs is clinically important, because the changes in the expression and activity of DMEs may affect the pharmacokinetics and pharmacodynamics of clinical drugs.

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Declaration of interest

The authors were supported in part by the National Institute of Health (NIH grant ES023438). The authors have no other 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 apart from those disclosed.