Back to Search
Start Over
Target-Mediated Drug Disposition-A Class Effect of Soluble Epoxide Hydrolase Inhibitors
- Source :
- J Clin Pharmacol
- Publication Year :
- 2020
-
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 human, 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 utilizing pharmacometric modeling in facilitating quantitative understanding of TMDD.
- Subjects :
- Pharmacology
Epoxide hydrolase 2
Epoxide Hydrolases
Drug disposition
Chemistry
Nonlinear pharmacokinetics
Phenylurea Compounds
Class effect
030226 pharmacology & pharmacy
Article
Clinical study
03 medical and health sciences
0302 clinical medicine
Drug development
Pharmacokinetics
Piperidines
In vivo
030220 oncology & carcinogenesis
cardiovascular system
Animals
Humans
Pharmacology (medical)
Subjects
Details
- ISSN :
- 15524604
- Volume :
- 61
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Journal of clinical pharmacology
- Accession number :
- edsair.doi.dedup.....a063e8b5953d183d391eb70be5b099b5