Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

https://doi.org/10.1016/j.pharmthera.2020.107627Get rights and content

Abstract

Inflammation is an evolutionary process that allows survival against acute infection or injury. Inflammation is also a pathophysiological condition shared by numerous chronic diseases. In addition, inflammation modulates important drug-metabolizing enzymes and transporters (DMETs), thus contributing to intra- and interindividual variability of drug exposure. A better knowledge of the impact of inflammation on drug metabolism and its related clinical consequences would help to personalize drug treatment.

Here, we summarize the kinetics of inflammatory mediators and the underlying transcriptional and post-transcriptional mechanisms by which they contribute to the inhibition of important DMETs. We also present an updated overview of the effect of inflammation on the pharmacokinetic parameters of most of the drugs that are DMET substrates, for which therapeutic drug monitoring is recommended. Furthermore, we provide opinions on how to integrate the inflammatory status into pharmacogenetics, therapeutic drug monitoring, and population pharmacokinetic strategies to improve the personalization of drug treatment for each patient.

Keywords

Inflammation
Drug metabolism
Drug transporters
Personalized medicine
Pharmacokinetics
Therapeutic drug monitoring

Abbreviations

ABC
ATP binding cassette
APP
acute phase protein
AUC
area under the curve
C/D
concentration/dose ratio
CKD
chronic kidney disease
Cmax
maximal concentration
Cmin
trough concentration
CAR
constitutive androstane/active receptor
CRP
C reactive protein
CYP
cytochrome P450
DAMP
damage-associated molecular pattern
DMET
drug metabolizing enzymes and transporters
FXR
farnesoid X receptor
IFN
interferon
IL
interleukin
LPS
lipopolysaccharide
MAPK
MAP kinases
MEGX
monoethylglycinexylidide
MPA
mycophenolic acid
NO
nitric oxide
PAMP
pathogen-associated molecular pattern
PPAR
peroxisome proliferator activation receptor
PXR
pregnane X receptor
RXR
retinoid X receptor-α
SLC
solute carriers
TDM
therapeutic drug monitoring
TLR
toll like receptor
TNF-α
tumor necrosis factor α
UDP-GT
UDP-glucuronyl transferase

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equal author contributions.

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