Journal article
Target-Mediated Drug Disposition-A Class Effect of Soluble Epoxide Hydrolase Inhibitors
Journal of clinical pharmacology, Vol.61(4), pp.531-537
04/2021
DOI: 10.1002/jcph.1763
PMCID: PMC7969377
PMID: 33078430
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.
Details
- Title: Subtitle
- Target-Mediated Drug Disposition-A Class Effect of Soluble Epoxide Hydrolase Inhibitors
- Creators
- Guohua An - University of IowaKin Sing Stephen Lee - Michigan State UniversityJun Yang - University of California, DavisBruce D Hammock - University of California, Davis
- Resource Type
- Journal article
- Publication Details
- Journal of clinical pharmacology, Vol.61(4), pp.531-537
- DOI
- 10.1002/jcph.1763
- PMID
- 33078430
- PMCID
- PMC7969377
- NLM abbreviation
- J Clin Pharmacol
- ISSN
- 0091-2700
- eISSN
- 1552-4604
- Grant note
- R00 ES024806 / NIEHS NIH HHS P42 ES004699 / NIEHS NIH HHS R35 ES030443 / NIEHS NIH HHS
- Language
- English
- Date published
- 04/2021
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984366017602771
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