Prediction of Oral Bioavailability

Oral bioavailability can be predicted using the following equation:

where Fa represents the fraction of drug absorbed through the intestinal lining, Cl is the hepatic clearance (predicted from in vitro studies, see earlier section) and Q is the hepatic blood flow in man (see, for example, Rane etal., 1977). Octanol/water partitioning has traditionally been used to predict the fraction absorbed through the intestinal lining. Recently, Caco-2 cell permeability studies have replaced the use of octanol/buffer partitioning studies. Yee (1997) established a relationship between Fa and Caco-2 cell permeability, expressed as the apparent permeability constant (Papp), as follows:

Papp < 10-6 cm/s, then Fa = 0 - 20% 1 < Papp < 10 x 10-6 cm/s, then Fa = 20 - 70% Papp > 10-5 cm/s, then Fa = > 70%

The use of Caco-2 cell permeability studies has resulted in more accurate oral bioavailability predictions. Using the predicted hepatic clearance for Compound X in man (see above), estimating Fa by extrapolation from the Caco-2 cell Papp, and an assumed hepatic blood flow for man (see, for example, Rane et al., 1977) of 20ml/min/kg, the human oral bioavailability of 69-98% for Compound X is predicted. This compares well with the known oral bioavailability of this compound in rats and dogs (83% and 72%, respectively).

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