Journal article
Target Abundance in Pharmacological Target-Mediated Drug Disposition (TMDD) for Small Molecules — A Proteomics Approach
The AAPS journal, Vol.28(1), p.45
01/06/2026
DOI: 10.1208/s12248-025-01182-y
PMID: 41495534
Appears in UI Libraries Support Open Access
Abstract
The phenomenon of nonlinear pharmacokinetics (PK) mediated by a drug’s pharmacological target, also known as target-mediated drug disposition (TMDD), has been increasingly observed in small molecules in the past decade. TMDD class effect with remarkably similar nonlinear PK behaviors has been reported in 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors, monoamine oxidase type B (MAO-B) inhibitors, and soluble epoxide hydrolase (sEH) inhibitors. We anticipated that the occurrence of TMDD class effect might be due to their target capacities falling within a specific range, where nonlinear PK mediated by target binding are more likely to be evident. To test our hypothesis, we employed a mass spectrometry (MS)-based global proteomics approach to quantify the absolute protein concentrations of 11β-HSD1, sEH, and MAO-B in different tissues across species. The estimated total amounts of 11β-HSD1, MAO-B, and sEH in humans were approximately 4994, 4629, and 4137 nmol, respectively. The comparable abundance levels of these proteins suggest that TMDD is more likely to be observed when a drug binds to a target within a specific range, potentially between 1000 nmol and 10000 nmol, which corresponds to nonlinear PK at doses of 1–10 mg for a compound with a molecular weight of 400 g/mol. Our study highlights the importance of early target quantification and provides valuable insights into predicting unusual nonlinear PK caused by TMDD. Additionally, this proteomics-based approach for quantifying absolute target capacity could serve as a valuable tool for both industry and academic researchers in investigating other pharmacological targets.
Graphical Abstract
Details
- Title: Subtitle
- Target Abundance in Pharmacological Target-Mediated Drug Disposition (TMDD) for Small Molecules — A Proteomics Approach
- Creators
- Min Xu - University of IowaXuanzhen Yuan - University of IowaPeizhi Li - University of IowaThanh Bach - University of IowaHao-Jie Zhu - University of MichiganGuohua An - University of Iowa, Pharmaceutical Sciences and Experimental Therapeutics
- Resource Type
- Journal article
- Publication Details
- The AAPS journal, Vol.28(1), p.45
- DOI
- 10.1208/s12248-025-01182-y
- PMID
- 41495534
- NLM abbreviation
- AAPS J
- ISSN
- 1550-7416
- eISSN
- 1550-7416
- Publisher
- Springer Nature
- Grant note
- Sparrow Pharmaceuticals, Inc.
This work was partially funded by Sparrow Pharmaceuticals, Inc.
- Language
- English
- Date published
- 01/06/2026
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9985104896602771
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