Abstract
Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes—and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response.
Highlights
The clinical outcome of drug treatments can vary greatly between individuals and even within the same individual
Since IL-18 is reported to mediate its effect through Kupffer cells [38], this can explain the lack of effect on CYPs in HepaRG or primary human hepatocytes (PHHs) cell models described by Rubin et al inclusion of nonparenchymal cells in model systems might increase the responsiveness to IL-1β and IL-18 and better reflect the potential effect these inflammatory cytokines may have in an intact human liver
Transcription factors involved in the regulation of CYP mRNA levels, including the nuclear receptors pregnane X receptor (PXR), the constitutive androstane receptor (CAR), their dimerization partner retinoid X receptor (RXR), the aryl hydrocarbon receptor (AhR), as well as human nuclear factors (HNFs) are held responsible for the observed downregulation of drug-metabolizing enzymes (DMEs) upon inflammation
Summary
The clinical outcome of drug treatments can vary greatly between individuals and even within the same individual. Through the use of in-vitro hepatocyte models, researchers have investigated which inflammatory mediators can be held responsible for the observed changes in drug metabolism These studies primarily emphasize the effects of inflammatory stimuli on either the mRNA expression of the major CYPs responsible for drug metabolism or the actual metabolism of probe substrates for these CYPs. Since DMEs show substantial interspecies differences in terms of metabolizing activity and isoform composition, rodent data may not be useful in extrapolation to the clinic [13]. Such differences in sensitivity are potentially important as these data suggest that drugs metabolized by CYP3A4 may be affected already at an earlier state during inflammation than drugs that rely on other CYP enzymes
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