275 300 325 350 WAVELENGTH (nm)

Figure 7.57 UV spectra of propranolol: (a,d) acceptor wells; (b,e) donor wells; (c,f) reference wells (pH 7.4, 47 mm).

with the concomitant decrease in membrane retention from 94% to 41%. Furthermore, the effective permeability rises to 25.1 x 10~6cm/s, more than a 10-fold increase, presumably due to the desorption effect of the surfactant. Only 3 h permeation time was used in the case (Figs. 7.57d-f). With such a sink at work, one can lower the permeation time to less than 2 h and still obtain very useful UV spectra. This is good for high-throughput requirements.

Figure 7.57a shows that reproducible absorbances can be measured with optical density (OD) values as low as 0.0008, based on a spectrophotometry pathlength of 0.45 cm. The baseline noise (OD in the range 350-500 nm in Fig. 7.57a) is estimated to be about ±0.0002 OD units.

7.8 THE OPTIMIZED PAMPA MODEL FOR THE GUT 7.8.1 Components of the Ideal GIT Model

The examination of over 50 PAMPA lipid models has led to an optimized model for gastrointestinal tract (GIT) absorption. Table 7.22 shows six properties of the GIT, which distinguish it from the blood-brain barrier (BBB) environment.

1. The in vitro measurements of permeability by the cultured-cell or PAMPA model underestimate true membrane permeability, because of the UWL, which ranges in thickness from 1500 to 2500 mm. The corresponding in vivo value is 30-100 mm in the GIT and nil in the BBB (Table 7.22). The consequence of this is that highly permeable molecules are (aqueous) diffusion limited in the in vitro assays, whereas the membrane-limited permeation is operative in the in vivo case. Correcting the in vitro data for the UWL effect is important for both GIT and BBB absorption modeling.

2. The in vivo environment of the GIT is characterized by a pH gradient; the pH value is constant at 7.4 in the receiving compartment (blood), and varying in the donor compartment (lumen) from —5 to —8 from the start to the end of the small intestine. In contrast, the BBB has a constant iso-pH 7.4. Modeling the two environments requires proper pH adjustment in the in vitro model, as indicated in Table 7.22.

3. The receiver compartment in the GIT has a strong sink condition, effected by serum proteins. In contrast, the BBB does not have a strong sink condition. In the GIT, lipophilic molecules are swept away from the site of absorption; in

TABLE 7.22 In Vitro Double-Sink PAMPA Models for GIT and BBB Targets
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