ABSTRACT
The experimental results for alprenolol are in complete agreement with the theoretical analysis. Higher bioavailability of alprenolol has been found when dosage is increased. This experimental finding is the result of saturation of the enzymatic activity (KM«Csub) at higher doses, which reduces the first-pass effect. Accordingly, the value of the hepatic extraction ratio, Eh, in equation (9.15) is lower
at higher doses. In some cases a reduction of the first-pass effect on bioavailability can be achieved. For instance, the administration of the semisuccinate ester of propranolol caused a dramatic increase of propranolol plasma levels due to reduction of the first-pass effect. However, attempts to reduce the first -pass effect may induce other problems. In the case of orally administered peptides biotransformed by proteases in the GI epithelium, the administration of protease inhibitors to suppress the biotransformation of peptides may allow the uptake of non-desirable substances of peptide structure like enterotoxins.
