Translational aspects of drug metabolism in inflammation and disease

Drug therapy is the cornerstone in treating most medical conditions. One major issue indrug therapy is the variability in drug efficacy and toxicity, which sometimes hinder safeand effective pharmacotherapy in the individual patient. Drug metabolism is altered byintrinsic and extrinsic factors like sex, genetics, and drug-drug interactions. Disease andinflammation have also been associated with altered expression and activity of drug-metabolizing enzymes. But is the drug-metabolizing capacity altered when the illness or inflammation is treated and normalized? We hypothesized that drug-metabolizing capacitynormalizes when the disease or inflammation is treated and normalized. This thesis summarizes the results from three papers, including five studies.

The objective of the first paper was to evaluate the current evidence on inflammationmediated modulation of drug-metabolizing enzymes and transporters. In a systematic review, we evaluated data from clinical studies and human in vitro systems. We find proinflammatory cytokines to strongly downregulate CYP enzymes in vitro. Similarly, in clinical studies we find inflammation and disease to cause a clinically significant decrease in drug-metabolizing activity, most importantly, cytochrome P450 (CYP) 3A4 enzyme. However, there is a large interindividual and intraindividual variability in the current literature. In addition, we identified a significant gap in translating in vitro studies to clinical studies; in vitro studies often use supraphysiological concentrations of pro-inflammatory cytokines, challenging the translation.

Diabetes development and progression are associated with low-grade inflammation. The second paper aims to assess the impact of diabetes and diabetes treatment on the activity of drug-metabolizing enzymes. Through comprehensive register-based studies in Danish and Scottish cohorts, we confirmed our previous finding that initiation of glucose-lowering treatment decreases the anticoagulant effect of warfarin. CYP2C9 and CYP3A4 metabolize warfarin, and the results suggest that the interaction might be caused via the CYP enzyme pathway and is intensified by the glucose-lowering effect. We were not able to confirm this hypothesis in a self-controlled, clinical pharmacokinetic trial in 10 patients with treatment-naïve type 2 diabetes. Initiation of metformin treatment did not alter the activity of six of the essential CYP enzymes. Other pathways must be investigated to gain mechanistic insight into the observed interaction. 

The third paper investigates the impact of interleukin-6 receptor antagonists (anti-IL6R; sarilumab or tocilizumab) on CYP enzyme activity in patients with rheumatoid arthritis, a high-grade inflammatory disease. The trial ended prematurely after including three patients. Interleukin (IL)-6 plays a pivotal role in CYP enzyme regulation, and the direct blockade of the IL-6 pathway by anti-IL-6R therapy leads to a clinically significant increase in CYP enzyme activity. However, we observed that the effect is only acute, and the CYP enzyme activity returns to previous levels during long-term treatment. These results were confirmed in a retrospective study assessing clinical samples from the Danish Rheumatologic Biobank. This novel observation needs to be replicated prospectively in a larger cohort.  

Our studies highlight that drug-metabolizing capacity is variable and the effect of inflammation might be impacted by factors like the grade of inflammation and the type of inflammation-modulating treatment. We could not confirm that altered CYP enzyme activity is involved in the clinically relevant decreased anticoagulant effect observed among chronic warfarin users during the initiation of glucose-lowering drugs. Further studies are warranted to gain a mechanistic understanding of this specific interaction. Among three patients with high-grade inflammation, we observed a clinically relevant change in CYP enzyme activity following inflammation-modulating treatment. However, the observed effect is only temporary. Overall, our results augment the understanding of drug-diseasedrug interactions. But further studies are required to understand the pathways by which inflammatory diseases affect drug-metabolizing enzymes. Additionally, insight into the interindividual variation is needed to personalize medicine to the increasing group of patients suffering from inflammatory conditions.