Target‐Mediated Drug Disposition—A Class Effect of Soluble Epoxide Hydrolase Inhibitors

Abstract

Pharmacological target‐mediated drug disposition (TMDD) represents a special source of nonlinear pharmacokinetics, and its occurrence in large‐molecule compounds has been well recognized because numerous protein drugs have been reported to have TMDD due to specific binding to their pharmacological targets. Although TMDD can also happen in small‐molecule compounds, it has been largely overlooked. In this mini‐review, we summarize the occurrence of TMDD that we discovered recently in a series of small‐molecule soluble epoxide hydrolase (sEH) inhibitors. Our journey started with an accidental discovery of target‐mediated kinetics of 1‐(1‐propanoylpiperidin‐4‐yl)‐3‐[4‐(trifluoromethoxy)phenyl]urea (TPPU), a potent sEH inhibitor, in a pilot clinical study. To confirm what we observed in humans, we conducted a series of mechanism experiments in animals, including pharmacokinetic experiments using sEH knockout mice as well as in vivo displacement experiments with co‐administration of another potent sEH inhibitor. Our mechanism studies confirmed that the TMDD of TPPU is due to its pharmacological target sEH. We further expanded our evaluation to various other sEH inhibitors and found that TMDD is a class effect of this group of small‐molecule sEH inhibitors. In addition to summarizing the occurrence of TMDD in sEH inhibitors, in this mini‐review we also highlighted the importance of recognizing TMDD of small‐molecule compounds and its impact in clinical development as well as using pharmacometric modeling in facilitating quantitative understanding of TMDD.

Species Differences in Metabolism of Soluble Epoxide Hydrolase Inhibitor, EC1728, Highlight the Importance of Clinically Relevant Screening Mechanisms in Drug Development

“…sEH inhibitors with these characteristics often demonstrate target-mediated drug disposition (TMDD) that results in observed efficacy independent of PK due to elimination largely resulting from the inhibitor binding the intracellular sEH enzyme with high affinity and thus removing it from detection in the plasma while still retaining a high level of enzyme inhibition. Similar sEHI have demonstrated TMDD properties, and these properties are often characteristic of drug classes [ 44 ]. Interpretation of efficacy results in compounds demonstrating TMDD are often more complicated than simple correlations of drug exposure translating to efficacious effects and may explain why low exposures of EC1728 after IV dosing results in acute analgesia in an inflammatory pain model in cats.…”

Importance of Target‐Mediated Drug Disposition (TMDD) of Small‐Molecule Compounds and Its Impact on Drug Development—Example of the Class Effect of HSD‐1 Inhibitors

“…Prior to 2010, there were scarce reports of small‐molecule TMDD 1,9 . The situation has changed in the past decade: with more and more potent small‐molecule compounds that act on highly specific targets in development, and with increasingly sensitive analytical instruments, the recognition of small‐molecule TMDD has increased significantly 10–18 . Moreover, TMDD appears to apply to some small‐molecule compound classes, as demonstrated in a series of small‐molecule soluble epoxide hydrolase (sEH) inhibitors, 15,19 as well as in a group of small‐molecule endothelin receptor antagonists (ERAs) 17 .…”

“…1,9 The situation has changed in the past decade: with more and more potent small-molecule compounds that act on highly specific targets in development, and with increasingly sensitive analytical instruments, the recognition of small-molecule TMDD has increased significantly. [10][11][12][13][14][15][16][17][18] Moreover, TMDD appears to apply to some smallmolecule compound classes, as demonstrated in a series of small-molecule soluble epoxide hydrolase (sEH) inhibitors, 15,19 as well as in a group of smallmolecule endothelin receptor antagonists (ERAs). 17 The main purpose of the current review is to increase the awareness of TMDD in a series of small-molecule inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1), an enzyme that in vivo converts inactive glucocorticoids (eg, cortisone, prednisone) to their active congeners (eg, cortisol, prednisolone).…”

Macrophage Inactivation by Small Molecule Wedelolactone via Targeting sEH for the Treatment of LPS-Induced Acute Lung Injury

“…It is metabolized by three main pathwayscytochrome P450s (CYPs, e.g., CYP3A and CYP2J), cyclooxygenases (COXs, e.g., COX-2), and lipoxygenases (LOXs, e.g., 12-LOX), into bioactive derivatives . Among bioactive derivatives of AA, epoxy fatty acids (EpFAs) represented by epoxyeicosatrienoic acids (EETs), produced by several CYP450 oxidases (e.g., CYP2J and CYP2C), have received great attention from scientists because of their outstanding physiological effects, especially anti-inflammatory, antioxidant, and antalgesic activities. − However, EETs are rapidly metabolized in the presence of epoxide hydrolases (EHs) represented by soluble epoxide hydrolase (sEH), which causes the loss of their multiple effects. ,− sEH, encoded by Ephx2 , is a bifunctional enzyme with 555 amino acid residues, and its C-terminal mediates the hydrolysis of bioactive epoxy fatty acids (EpFAs), such as EETs and epoxydocosapentaenoic acids (EDPs), , while the role of the N-terminal phosphatase is poorly understood. Recently, sEH inhibition to enhance levels of EETs has become an attractive research strategy to treat diseases related to inflammation, such as lung injury and diabetes. − …”