Paper Pick – Intestinal Secretion Is a Potentially Important Clearance Mechanism for Low Metabolic Clearance Compounds
In this paper, scientists at Gilead uncover the propensity of drug-like molecules with lower systemic clearance to be eliminated through intestinal excretion (IE) directly into the lumen via enterocytes.
From a study with 90 compounds in late lead optimization, IE was found to be specifically relevant for those with low metabolic clearance in conjunction with:
- moderate/high plasma binding,
- low/moderate passive permeability, and
- low biliary excretion.
This equated to about 10-15% of the compounds examined, and for which intestinal excretion should be considered for human dose projections. In particular, it is advised that IE should be considered for ultrastable compounds designed for extended use.
The class of compounds deemed more likely to undergo IE are part of ECCS Class 3B, and potentially some from Class 3A and 4 [1]. All of these were postulated to undergo renal or transporter mediated clearance.
Interestingly the authors highlight that compounds likely to undergo IE are those that are not subject to typical metabolic clearance pathways. Hence it was proposed that IE could be seen more as a likely “salvage” clearance pathway for these compounds.
The relevance of this work is clear as efforts by medicinal chemists to design drug scaffolds super stable to the metabolic mechanisms commonly encountered in the liver.
It would be interesting to look at how IE impacts not only the population and diversity of gut microflora, but also whether the compounds remain stable to a different repertoire of enzyme reactions in the anaerobic environment of the lower gut.
Paper
Subramanian, M., Ahire, D., Tanna, R., Yu, Z. J., Wang, K., Wang, W., Smith, G., & Liu, X. (2025). Intestinal Secretion Is a Potentially Important Clearance Mechanism for Low Metabolic Clearance Compounds. Journal of medicinal chemistry, 68(11), 11820–11828. https://doi.org/10.1021/acs.jmedchem.5c00671
[1] ECCS Framework
Extended Clearance Classification System (ECCS) – used to predict the predominant clearance mechanism (rate-determining process) based on physicochemical properties and passive membrane permeability.
Compound classifications:
- Class 1A – metabolism as primary systemic clearance mechanism (high permeability acids/zwitterions with molecular weight (MW) ≤400 Da)
- Class 1B – transporter-mediated hepatic uptake as primary systemic clearance mechanism (high permeability acids/zwitterions with MW >400 Da)
- Class 2 – metabolism as primary clearance mechanism (high permeability bases/neutrals)
- Class 3A – renal clearance (low permeability acids/zwitterions with MW ≤400 Da), Class 3B–transporter mediated hepatic uptake or renal clearance (low permeability acids/zwitterions with MW >400 Da)
- Class 4 – renal clearance (low permeability bases/neutrals).
Varma, M. V., Steyn, S. J., Allerton, C., & El-Kattan, A. F. (2015). Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS). Pharmaceutical research, 32(12), 3785–3802. https://doi.org/10.1007/s11095-015-1749-4
