PMID- 33078430
OWN - NLM
STAT- MEDLINE
DCOM- 20211220
LR  - 20220402
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Print)
IS  - 0091-2700 (Linking)
VI  - 61
IP  - 4
DP  - 2021 Apr
TI  - Target-Mediated Drug Disposition-A Class Effect of Soluble Epoxide Hydrolase 
      Inhibitors.
PG  - 531-537
LID - 10.1002/jcph.1763 [doi]
AB  - 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.
CI  - (c) 2020, The American College of Clinical Pharmacology.
FAU - An, Guohua
AU  - An G
AUID- ORCID: 0000-0002-6498-7663
AD  - Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, 
      University of Iowa, Iowa, Iowa, USA.
FAU - Lee, Kin Sing Stephen
AU  - Lee KSS
AD  - Department of Pharmacology and Toxicology, Michigan State University, East 
      Lansing, Michigan, USA.
AD  - Department of Chemistry, Michigan State University, East Lansing, Michigan, USA.
FAU - Yang, Jun
AU  - Yang J
AD  - Department of Entomology and Nematology and UCD Cancer Research Center, 
      University of California at Davis, Davis, California, USA.
FAU - Hammock, Bruce D
AU  - Hammock BD
AD  - Department of Entomology and Nematology and UCD Cancer Research Center, 
      University of California at Davis, Davis, California, USA.
LA  - eng
GR  - P42 ES004699/ES/NIEHS NIH HHS/United States
GR  - R00 ES024806/ES/NIEHS NIH HHS/United States
GR  - R35 ES030443/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
DEP - 20201019
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Piperidines)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Animals
MH  - Epoxide Hydrolases/*antagonists & inhibitors
MH  - Humans
MH  - Phenylurea Compounds/*pharmacokinetics
MH  - Piperidines/*pharmacokinetics
PMC - PMC7969377
MID - NIHMS1643100
OTO - NOTNLM
OT  - drug development
OT  - nonlinear pharmacokinetics
OT  - soluble epoxide hydrolase inhibitors
OT  - target-mediated drug disposition
EDAT- 2020/10/21 06:00
MHDA- 2021/12/21 06:00
PMCR- 2022/04/01
CRDT- 2020/10/20 06:27
PHST- 2020/08/10 00:00 [received]
PHST- 2020/09/23 00:00 [accepted]
PHST- 2020/10/21 06:00 [pubmed]
PHST- 2021/12/21 06:00 [medline]
PHST- 2020/10/20 06:27 [entrez]
PHST- 2022/04/01 00:00 [pmc-release]
AID - 10.1002/jcph.1763 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2021 Apr;61(4):531-537. doi: 10.1002/jcph.1763. Epub 2020 Oct 
      19.