Potential pharmacokinetic interactions of therapeutic cytokines or cytokine modulators on small-molecule drugs: mechanistic understanding via studies using in vitro systems

Abstract

The potential pharmacokinetic interactions between macromolecules and small-molecule drugs have received more and more attention with the increasing development of macromolecule therapeutics. Studies have shown that cytokines can differentially modulate drug-metabolizing enzymes and transporters, which raises concerns on the potential interactions of therapeutic cytokines and cytokine modulators on the disposition of small-molecule drugs. Although many in vitro studies have been conducted to characterize the effects of cytokines on drug-metabolizing enzymes and transporters, these studies were limited to only a handful of cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-α, and interferon. It is also challenging to translate these in vitro results to in vivo. In addition, information on the impact of cytokine modulators on drug-metabolizing enzymes and transporters is rather limited. More research is needed in this area. The present review is to provide a summary of the in vitro findings on the pharmacokinetic interactions of therapeutic cytokines and cytokine modulators on small-molecule drugs. Discussion on current challenges in assessing these interactions is also included.

Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics

“…Therefore, in-vitro liver models may be valuable tools to elucidate the specific effects of inflammation on drug metabolism. Earlier studies with in-vitro models have already demonstrated that various inflammatory mediators associated with inflammation and infection can modulate drug metabolism by reducing the expression of CYPs [2,3,11,12]. However, since the effect of inflammation-induced phenoconversion depends on the degree and type of inflammation as well as the metabolic pathway of the drug, it is necessary to better understand the different effects of various pro-inflammatory mediators and focus on the differential sensitivity between CYP isoforms in response to them.…”

Modeling Therapeutic Antibody–Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

“…Inflammation is known to down-regulate CYP activity, a normal adaptation to a stressed state mediated by transcription factors such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and nuclear factor kB (NF-kB) as well as reactive oxygen species (Morgan et al, 2008). Inflammatory cytokines have been linked to the suppression of specific CYP enzymes Zhou and Li, 2014), which has potential implications for modulating drug exposure and thus safety.…”

Interactions between Cytokines and Drugs in COVID-19 Potential Interactions between Increased Cytokines in COVID-19 and Drugs used to Treat COVID-19

“…In 1978, Chang et al [52], for the first time reported that drug pharmacokinetics changed in humans under inflammation and infection conditions, and this change was later attributed to the effects of cytokines on hepatic CYP enzymes [53]. Studies on how cytokines affect different CYP enzymes are primarily in vivo experiments or in vitro cell cultures with lipopolysaccharide (LPS) and experimental models including different inflammatory mechanisms created by the administration of active virus or direct cytokines [11,[52][53][54][55]. These interactions in humans have mostly been studied in patients with chronic inflammation [13,21,56,57].…”

“…In these studies, IL-6, IL-1, TNF, and IFN downregulate mRNA or reduce the activity of essential CYP enzymes. Zhou J and Li F [55], summarized eleven studies involving the effects of cytokines on different CYPs in primary cultured human hepatocytes. The effects of cytokines on CYP enzymes in human hepatocytes were investigated in an extensive in vitro study by Aetkins et al [14].…”