Inflammation Downregulates Drug-Metabolising Enzymes: Implications for Therapeutic Drug Monitoring
This systematic review of 203 studies demonstrates that inflammatory cytokines IL-6 and IL-1-beta substantially downregulate CYP3A4 and, to a lesser extent, CYP1A2, CYP2C9, CYP2C19, and CYP2D6 in both hepatocyte models and clinical inflammatory conditions. The resulting altered drug metabolism is clinically relevant for narrow therapeutic index medications. The findings highlight why pharmacogenomic predictions alone may be insufficient and why therapeutic drug monitoring remains essential in patients with active inflammation.
The original study
Clinical and Molecular Perspectives on Inflammation-Mediated Regulation of Drug Metabolism and Transport.
- Authors
- Dunvald AD, Järvinen E, Mortensen C, Stage TB
- Journal
- Clinical pharmacology and therapeutics
- Type
- Journal Article, Review, Research Support, Non-U.S. Gov't
- PMID
- 34605009
Original abstract
Inflammation is a possible cause of variability in drug response and toxicity due to altered regulation in drug-metabolizing enzymes and transporters (DMETs) in humans. Here, we evaluate the clinical and in vitro evidence on inflammation-mediated modulation of DMETs, and the impact on drug metabolism in humans. Furthermore, we identify and discuss the gaps in our current knowledge. A systematic literature search on PubMed, Embase, and grey literature was performed in the period of February to September 2020. A total of 203 papers was included. In vitro studies in primary human hepatocytes revealed strong evidence that CYP3A4 is strongly downregulated by inflammatory cytokines IL-6 and IL-1β. CYP1A2, CYP2C9, CYP2C19, and CYP2D6 were downregulated to a lesser extent. In clinical studies, acute and chronic inflammatory diseases were observed to cause downregulation of CYP enzymes in a similar pattern. However, there is no clear correlation between in vitro studies and clinical studies, mainly because most in vitro studies use supraphysiological cytokine doses. Moreover, clinical studies demonstrate considerable variability in terms of methodology and inconsistencies in evaluation of the inflammatory state. In conclusion, we find inflammation and pro-inflammatory cytokines to be important factors in regulation of drug-metabolizing enzymes and transporters. The observed downregulation is clinically relevant, and we emphasize caution when treating patients in an inflammatory state with narrow therapeutic index drugs. Further research is needed to identify the full extent of inflammation-mediated changes in DMETs and to further support personalized medicine.