Laura de Jong obtained both her Bachelor’s and Master’s degrees in Bio-Pharmaceutical Sciences from Leiden University, achieving the highest distinction (summa cum laude) for her Master’s degree. During her internship at the Leiden Academic Centre for Drug Research, she investigated a potential novel target in atherosclerosis using a mouse model. At Janssen, she focussed on developing a high-throughput nanoBRET assay for characterization of proteolysis targeting chimera (PROTAC) ternary complex formation.  Currently, she is a third year PhD student at the Leiden Academic Centre for Drug Research under the supervision of Dr. Martijn Manson and Prof. Dr. Jesse Swen. Within the division of System Pharmacology & Pharmacy, her focus lies on gaining a deeper understanding of how non-genetic factors, such as inflammation and concomitant medication use, impact drug metabolism. Ultimately, this research may help to improve our ability to predict individual drug metabolism and personalize drug treatment. This research involves close collaboration with the hospital pharmacy at the Leiden University Medical Center (LUMC) to facilitate translation of these findings to-and from the clinic. 

Pro-inflammatory cytokine release observed in acute or chronic inflammatory conditions leads to compromised metabolism of drugs in the liver. Inhibition of cytochrome P450 (CYP450) enzymes is believed to be the primary cause of inflammation-driven changes in metabolic capacity. However, it remains unclear to what degree inflammation affects other classes of drug-metabolizing enzymes (DMEs), such as the flavin monooxygenases (FMOs) and uridine 5'-diphospho-glucuronosyltransferases (UGTs). To address this issue, our study aims to quantify changes in DMEs at both the transcriptional and activity levels following treatment with physiologically relevant concentrations of pro-inflammatory cytokines IL-6 and IL-1β in HepaRG cells, which have emerged as a valuable tool to study drug metabolism due to long-term stable and high expression of DMEs. This present study emphasizes that inflammation differentially impacts the various DME families CYPs, FMOs and UGTs on both a transcriptional and activity level. Compared to CYP3A4, enzymes from both the FMO family (FMO3/FMO4) and from the UGT family (UGT1A4/UGT2B4/UGT2B7) are less sensitivity towards IL-6 and IL-1β induced downregulation. These results implicate that risk assessment on under- or overexposure during inflammation should consider the metabolic routes of a drug.