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

Abstract

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

Conflict of interest statement

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.

Figures

Figure 1

Schematic representation of correlation between disease-mediated alteration in drug metabolizing enzymes and small molecule drug levels

Figure 2

Percentage of major classes of biologics approved by U.S FDA (2016)

Figure 3

Clinical biologic-DDIs included in labelling approved by FDA (2016)

Figure 4

Mechanism of Biologics-SMDs interaction. 1) In infection/inflammation disease states, plasma levels of cytokines/chemokines/peptides and growth factors are elevated. These factors act on the liver to activate kupffer cells to release pro-inflammatory cytokines. These intrinsic as well as the circulatory cytokines act on the hepatocytes through the cytokine receptors. Furthermore, the TLRs on the hepatocytes are activated, to induce cell-signaling pathways, leading to the down-regulation of basal transcription factors, NRs and DMEs. This leads to disruption of drug metabolism/clearance. 2) Upon treatment with biologics which are immunostimulators, cytokines in the liver are elevated further, thus potentiating the down-regulation of DMEs, causing more severe disruption of drug metabolism/clearance and increasing the levels of SMDs. 3) In contrast, biologics which are immunosuppressors, attenuate inflammatory disease-mediated elevation of cytokines and restore the expression/activity of DMEs and ultimately levels of SMDs are neutralized.