Figure 5.3. Correlation of PAMPA permeability with Caco-2 cell permeability for ~100 internal research compounds from the Bristol-Myers Squibb labs. Each point is the mean of three or more repeats
or efflux transporters are involved. And the follow-up studies using more mechanistic models (e.g., cell line with specific transporter expressed, xenopus oocytes, etc.) might be warranted.
A combination of PAMPA and Caco-2 cells is often used to assess the permeability of test compounds in the most cost-effective manner (Ano et al., 2004; Kerns et al., 2004). PAMPA model is preferred by virtue of its easy set-up and rapid operation. It is a low cost assay (cost per test is a fraction of Caco-2 cells cost) and is less resource and time intensive. Automated robotic driven PAMPA model is capable of screening thousands of compounds per week. Caco-2 cells, on the other hand, is a cost and resource intensive assay and not amenable to ultra HTS. To obtain the maximum permeability/absorption information in the least amount of time with minimal use of resources, a combination of PAMPA along with unidirectional Caco-2 cells (A to B permeability) is increasingly becoming popular. Figure 5.4a shows the Caco-2 cell permeability values obtained for a series of compounds within a chemotype from a typical research program. The majority of the compounds had "low" permeability values below 100nm/s in the Caco-2 cell model. These compounds with low Caco-2 cell permeability would generally be assumed to be poorly absorbed in humans and may not make the initial cut to move forward (i.e., low priority). However, a combination assay (PAMPA and unidirectional Caco-2 cell) provided a better understanding of the
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