Target Abundance in Pharmacological Target-Mediated Drug Disposition (TMDD) for Small Molecules — A Proteomics Approach

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.