Permeation prediction of M100240 using the parallel artificial membrane permeability assay.
OBJECTIVE
Kansy et al first introduced the Parallel artificial membrane permeation assay (PAMPA) in 1998. In this system, the permeability through a membrane formed by a mixture of lecithin and an inert organic solvent on a filter support is assessed. PAMPA shows definite trends in the ability of molecules to permeate membranes by transcellular passive diffusion. Its simplicity, low cost, high throughput, and wide pH range make it very attractive in modern drug discovery. Based on this concept, Whohnsland et al, Sugano et al and Zhu et al modified the assay and used it to screen compound permeability. We used PAMPA for the permeation prediction of M100240, which was unable to be determined by cell-based assays due to compound instability.


METHODS
In this study, 92 commercially available agents provided the structural diversity used to generate a mathematical prediction model for human fraction absorbed, M100240--an acetate thioester of MDL 100,173. Permeation of M100240 and MDL 100,173 was evaluated using the parallel artificial membrane permeability assay (PAMPA). The donor and recipient solutions consisted of 0.5N HCl (pH 1.5) or phosphate-buffered saline (pH 5.5 or 7.4) with 2% dimethyl sulfoxide. The donor solution also contained 200 mM M100240 or MDL 100,173.


RESULTS
M100240 had a medium permeation at pH 5.5 (2.99%), corresponding to a high predicted Fa in humans (92%). Permeation of MDL 100,173 was low at this pH (0.72%), corresponding to a medium-to-low predicted Fa (46). At pH 7.4, the permeation of M100240 was low (approximately 1%) and no permeation was apparent for MDL 100,173.


CONCLUSIONS
We predicted M100240 is likely to be well absorbed via passive diffusion across the human gastrointestinal tract following oral administration.
Hwang
Kin-Kai
KK
Department of Drug Metabolism and Pharmacokinetics, Aventis Pharmaceuticals Inc., Bridgewater, New Jersey, USA. kinkai.hwang@aventis.com
Martin
Nancy E
NE
Jiang
Lan
L
Zhu
Chengyue
C
D001552:Benzazepines / Q000737:chemistry / Q000493:pharmacokinetics*; D002463:Cell Membrane Permeability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008567:Membranes, Artificial; D010539:Permeability; D011237:Predictive Value of Tests; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics*
D001552:Benzazepines; D008567:Membranes, Artificial; D011725:Pyridines; C085683:MDL 100240; C085684:MDL 100173