Regions of Limited Bioavailability

From the contour plot in Figure 4, we can identify three reasons for limited bioavailability. The upper right-hand corner (high Do, high Dn) is the region of solubility-limited absorption. As explained in the above section, this occurs when saturation solubility in the intestinal medium is reached.

In the lower left-hand corner (low Do, low Dn) is the region of dissolution-limited absorption. The dissolution rate is slower than the absorption rate and therefore dissolution is the rate-limiting step for bioavailability.

In the lower right-hand corner (low Do, high Dn) is the region of permeability-limited absorption. Low permeability (low An) controls bioavailability and although dose and dissolution rate are optimal, one can only absorb a fraction of the dose - in the example of Figure 4, about 70%. At the lower limit of paracellular permeability, An ^ 0.3 which results in a maximum Fabs ^ 0.45 for permeability-limited absorption.

The key premise of this discussion is that where you are located in the biopharmaceutic landscape determines what formulation strategy you should employ to enhance bioavail-ability.

S = Solubility Limited _

D = Dissolution Limited O P = Permeability Limited

Figure 4. Contour plot of fraction absorbed (Fabs) for a low permeability compound showing the different regions of limiting bioavailability.

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Figure 4. Contour plot of fraction absorbed (Fabs) for a low permeability compound showing the different regions of limiting bioavailability.

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