Inflammation Induces Changes in the Functional Expression of P-gp, BCRP, and MRP2: An Overview of Different Models and Consequences for Drug Disposition

Abstract

The ATP-binding cassette (ABC) transporters play a key role in drug pharmacokinetics. These membrane transporters expressed within physiological barriers can be a source of pharmacokinetic variability. Changes in ABC transporter expression and functionality may consequently affect the disposition of substrate drugs, resulting in different drug exposure. Inflammation, present in several acute and chronic diseases, has been identified as a source of modulation in drug transporter expression leading to variability in drug response. Its regulation may be particularly dangerous for drugs with a narrow therapeutic index. In this context, numerous in vitro and in vivo models have shown up- or downregulation in the expression and functionality of ABC transporters under inflammatory conditions. Nevertheless, the existence of contradictory data and the lack of standardization for the models used have led to a less conclusive interpretation of these data.

Pharmacokinetic Imaging Using 99mTc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats

“…Disruption of hepatocyte transporter function by inflammation is increasingly considered as a cause of disease-related changes in liver function, hepatobiliary elimination of drugs, PK, and toxicity [3,8]. Dysregulation of hepatocyte transporters and cytochromes has been reported during endotoxin-mediated inflammation induced by lipopolysaccharide (LPS) in vitro [9] and ex vivo, in several animal species [10][11][12][13]. In animal models, the impaired activity of ABC transporters during inflammation has been linked to cholestasis and/or abnormal liver accumulation of drugs and metabolites, which may provide a mechanistical explanation for drug-induced liver injury (DILI) [14].…”

TNF-α and IL-1β Exposure Modulates the Expression and Functionality of P-Glycoprotein in Intestinal and Renal Barriers

“…Inflammatory mechanisms lead to an increased systemic cytokine concentration including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNFα), and interferon (IFN). 10,11 It is known that these proinflammatory cytokines play a key role in the modulation of the expression of drug-metabolizing enzymes (DMEs) and drug transporters. 10−12 The release of cytokines can exert systemic effects through their interaction with the membrane receptors of epithelial or endothelial cells.…”

“…Mechanistically, the binding of cytokines to receptors induces a complex intracellular signaling cascade that ultimately modulates the expression of genes. 11 ABC transporters during inflammation have been reported in both preclinical and clinical studies. 13−15 Among ABC transporters, P-gp plays a key role in the pharmacokinetics of many drug classes such as anticancer agents, cardiovascular drugs, and anticoagulants.…”

“…Various sources of transporter modulation, including drug–drug interactions or genetic polymorphisms, have been reported, leading to clinically relevant pharmacokinetics variations. − Interestingly, ABC transporters can also be modulated by other stimuli. Inflammatory mechanisms lead to an increased systemic cytokine concentration including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), and interferon (IFN). , It is known that these pro-inflammatory cytokines play a key role in the modulation of the expression of drug-metabolizing enzymes (DMEs) and drug transporters. − The release of cytokines can exert systemic effects through their interaction with the membrane receptors of epithelial or endothelial cells. Mechanistically, the binding of cytokines to receptors induces a complex intracellular signaling cascade that ultimately modulates the expression of genes .…”

“…Inflammatory mechanisms lead to an increased systemic cytokine concentration including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), and interferon (IFN). , It is known that these pro-inflammatory cytokines play a key role in the modulation of the expression of drug-metabolizing enzymes (DMEs) and drug transporters. − The release of cytokines can exert systemic effects through their interaction with the membrane receptors of epithelial or endothelial cells. Mechanistically, the binding of cytokines to receptors induces a complex intracellular signaling cascade that ultimately modulates the expression of genes . Therefore, up- and downregulations of ABC transporters during inflammation have been reported in both preclinical and clinical studies. − Among ABC transporters, P -gp plays a key role in the pharmacokinetics of many drug classes such as anticancer agents, cardiovascular drugs, and anticoagulants.…”