Hwang Kin-Kai, Martin Nancy E, Jiang Lan, Zhu Chengyue
Department of Drug Metabolism and Pharmacokinetics, Aventis Pharmaceuticals Inc., Bridgewater, New Jersey, USA.
J Pharm Pharm Sci. 2003 Sep-Dec;6(3):315-20.
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.
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.
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.
We predicted M100240 is likely to be well absorbed via passive diffusion across the human gastrointestinal tract following oral administration.
1998年，坎西等人首次引入了平行人工膜渗透试验（PAMPA）。在该系统中，评估了通过由卵磷脂和惰性有机溶剂的混合物在滤膜载体上形成的膜的渗透性。PAMPA在分子通过跨细胞被动扩散渗透膜的能力方面显示出明确的趋势。其简单性、低成本、高通量和宽pH范围使其在现代药物发现中非常有吸引力。基于这一概念，霍恩斯兰德等人、菅野等人和朱等人对该试验进行了改进，并将其用于筛选化合物的渗透性。我们使用PAMPA对M100240的渗透性进行预测，由于化合物不稳定，基于细胞的试验无法确定该渗透性。
在本研究中，92种市售药物提供了用于生成人吸收分数数学预测模型的结构多样性，M100240是MDL 100,173的乙酸硫酯。使用平行人工膜渗透性试验（PAMPA）评估M100240和MDL 100,173的渗透性。供体和受体溶液由0.5N盐酸（pH 1.5）或磷酸盐缓冲盐水（pH 5.5或7.4）与2%二甲基亚砜组成。供体溶液还含有200 mM M100240或MDL 100,173。
M100240在pH 5.5时具有中等渗透性（2.99%），对应于人中较高的预测吸收分数（92%）。在此pH值下，MDL 100,173的渗透性较低（0.72%），对应于中低预测吸收分数（46）。在pH 7.4时，M100240的渗透性较低（约1%），MDL 100,173无明显渗透性。
我们预测口服给药后，M100240可能通过被动扩散在人胃肠道中被良好吸收。
