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.
journal_name
J Clin Pharmacoljournal_title
Journal of clinical pharmacologyauthors
An G,Lee KSS,Yang J,Hammock BDdoi
10.1002/jcph.1763subject
Has Abstractpub_date
2020-10-19 00:00:00eissn
0091-2700issn
1552-4604pub_type
杂志文章abstract：:Disease states such as liver cirrhosis and chronic kidney disease can lead to altered pharmacokinetics (PK) of drugs by influencing drug absorption, blood flow to organs, plasma protein binding, apparent volume of distribution, and drug-metabolizing enzyme and transporter (DMET) abundance. Narrow therapeutic index dru...
journal_title：Journal of clinical pharmacology
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abstract：:The effect of lovastatin given before percutaneous coronary angioplasty (PTCA) on early restenosis was investigated in men with mild to moderate hypercholesterolemia. Thirty-four hypercholesterolemic patients (serum LDL cholesterol 130-200 mg/dL) undergoing their first PTCA completed a 6-month prospective, double-blin...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章
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journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章,多中心研究,随机对照试验
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journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,多中心研究,随机对照试验
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journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,多中心研究,随机对照试验
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