Permeation prediction of M100240 using the parallel artificial membrane permeability assay

Area of Science:

• Pharmacokinetics and Drug Discovery
• Membrane Permeation Assays
• Computational Chemistry

Background:

• The Parallel Artificial Membrane Permeation Assay (PAMPA) was introduced in 1998 for assessing passive diffusion across membranes.
• PAMPA offers simplicity, low cost, high throughput, and a wide pH range, making it attractive for drug discovery.
• Modifications by Whohnsland et al., Sugano et al., and Zhu et al. have refined PAMPA for compound permeability screening.

Purpose of the Study:

• To evaluate the permeation of M100240, a compound whose permeability could not be determined by cell-based assays due to instability.
• To predict the human fraction absorbed (Fa) for M100240 using PAMPA.
• To compare the permeation of M100240 with MDL 100,173 using PAMPA.

Main Methods:

• Utilized 92 diverse, commercially available agents to develop a mathematical model for predicting human fraction absorbed.
• Employed the Parallel Artificial Membrane Permeation Assay (PAMPA) to assess the permeation of M100240 and MDL 100,173.
• Tested permeation across artificial membranes using donor solutions of 0.5N HCl (pH 1.5) or phosphate-buffered saline (pH 5.5 or 7.4) with 2% dimethyl sulfoxide.

Main Results:

• M100240 exhibited medium permeation at pH 5.5 (2.99%), predicting a high human fraction absorbed (Fa) of 92%.
• MDL 100,173 showed low permeation at pH 5.5 (0.72%), predicting a medium-to-low Fa of 46%.
• At pH 7.4, M100240 showed low permeation (approx. 1%), and MDL 100,173 showed no apparent permeation.

Conclusions:

• M100240 is predicted to be well absorbed via passive diffusion in the human gastrointestinal tract after oral administration.
• PAMPA is a viable method for predicting oral absorption of compounds that are unstable in cell-based assays.
• The study highlights the utility of PAMPA in drug discovery for assessing passive membrane permeability and predicting oral bioavailability.