Figure 7.65 Human intestinal absorption compared to Caco-2 permeabilities from Yazdanian's group [602].

solubility. The results from Irvine et al. [604] and Yamashita et al. [82] place nadolol on the best-fit curve (dashed line). The pharmacokinetic data indicates low HIA for nadolol, possibly due to P-gp efflux attenuating absorption. The Caco-2 result from Yazdanian's group may be high because of the use of high drug concentrations, enough to saturate the P-gp transport in Caco-2. There appears to be no consensus on what sample concentrations to use in Caco-2 assays, and every laboratory appears to have slightly different protocols, when it comes to Caco-2 measurements.

7.8.5 Novartis max-Pe PAMPA Model for Prediction of Human Intestinal Absorption (HIA)

The PAMPA strategy to predict HIA is based on recognizing that gradient pH conditions need to be incorporated into the in vitro models, and that the donor pH values must reflect the properties of the entire GIT (Table 7.2 and Fig. 2.3). Weak acids ought to be better absorbed in the jejunum, where the pH is well below 7.4. However, at the low pH, weak bases may not be well absorbed, since they are positively charged. In the ileum, where the pH may be as high as 8, the absorption of weak bases should be higher than that of weak acids, since the fraction of uncharged form of the bases will be higher at pH 8, compared to pH 5.

In a screening application, where the acid-base properties of discovery molecules may not be certain, it is necessary to screen at least at two pH values, to reflect the conditions of the small intestine. The higher of the two measured permeabilities can then be used to predict HIA. For example, if pH 5 and 7.4 were the two pH values in the PAMPA assay, a weak acid may show very high Pe at pH 5 but a very low Pe at pH 7.4. A single-pH assay at pH 7.4 may have classed the weak acid as a negative, whereas its absorption may have been excellent in the jejunum (pH 5), but this would not have been recognized in the single-pH assay. If a two-pH PAMPA assay is used, then the selection of the maximum Pe of the two measured values would avoid the case of false negatives. This strategy was recognized by Avdeef [26], Faller and Wohnsland [509,554], and Zhu et al. [549]. Figure 7.66 shows the plot of percent absorption versus PAMPA %flux [509]. Figure 7.66a shows the values were taken from just a single pH 6.8; Fig. 7.66b shows the correlation when the max-Pe value is selected from the range pH 5-8. The 50-70% absorption region, shows improvement in the max-Pe model (Fig. 7.66b).

7.8.6 pION Sum-Pe PAMPA Model for Prediction of Human Intestinal Absorption (HIA)

The preceding section can be further generalized, to properly account for absorption of nonionized molecules. The selection of the maximum Pe for HIA prediction implicitly recognized that only a fraction of the small intestine is available for the maximum absorption of acids (with pKa near 4) and bases (with pKa near 9). But when this approach is applied to nonionizable molecules, then the absorption may be underestimated, since absorption should be uniform across the whole intestinal tract. The remedy is to sum the two Pe values. This is roughly equivalent to

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