Can membrane permeability of zwitterionic compounds be predicted by the solubility-diffusion model?

Area of Science:

• Pharmacology
• Biophysics
• Computational Chemistry

Background:

• Zwitterions possess both positive and negative charges, resulting in a net neutral charge.
• The membrane permeability of zwitterionic compounds is often assumed to be lower than their neutral counterparts.
• It remains unclear whether zwitterionic or neutral forms dominate drug permeability, complicating in silico predictions.

Purpose of the Study:

• To re-evaluate existing in vitro permeability data for zwitterionic compounds.
• To determine the dominant species responsible for membrane permeability in zwitterionic drugs.
• To assess the predictability of zwitterionic compound permeability using the solubility-diffusion model.

Main Methods:

• Re-evaluation of literature data from Caco-2/MDCK cell assays.
• Application of strict exclusion criteria to filter out confounding transport effects.
• Analysis using the solubility-diffusion model to predict intrinsic permeabilities.

Main Results:

• Intrinsic permeabilities of the neutral fraction were accurately predicted by the solubility-diffusion model (RMSE = 1.21; n = 18).
• The permeability of the zwitterionic species was found to be negligible.
• The study demonstrates that only the neutral species is relevant for membrane permeability.

Conclusions:

• Membrane permeability of zwitterionic compounds is primarily governed by their neutral form.
• The solubility-diffusion model can effectively predict the membrane permeability of zwitterionic compounds.
• This research simplifies in silico permeability predictions for zwitterionic pharmaceuticals.