Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics–small molecule drug interactions

ABSTRACT

Introduction: Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment.

Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted.

Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

KEYWORDS:

• Biologics
• small molecule drugs
• drug-drug interaction
• drug metabolizing enzymes
• cytokines
• inflammation
• infection
• toll-like receptors
• nuclear receptors
• interferon

Article highlights

• Drug metabolism is disrupted due to down-regulation of enzymes and transporters during infectious and inflammatory diseases.

• Patients undergoing treatment with biologics may have altered metabolism of small molecule drugs due to alterations in expression/activity of the enzymes and transporters.

• Clinical drug interactions have been reported for several biologics including cytokines, growth factors, monoclonal antibodies, etc.

• The mechanism of alterations in enzymes/transporters by biologics during infection and inflammation needs further investigation.

• Increased use of biologics pose a higher risk of biologic-small molecule drug interactions in patients.

This box summarizes key points contained in the article.

Declaration of interest

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.

Additional information

Funding

U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, HL-112516, HL129794; U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Environmental Health Sciences, ES-009132, ES-019689; U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse DA035751