ABSTRACT
Agents and Dosage Forms toward Luminal Enzymatic Attack....................... 95
5.2.4.1 In Vitro Test Models for Luminally Secreted Enzymes ..................... 95
5.2.4.2 In Vitro TestModels for Brush BorderMembrane-Bound Enzymes ... 97
5.2.4.3 In Situ Test Models ............................................................................ 97
5.2.4.4 In Vivo Test Models ........................................................................... 97
5.3 Secretory Transport .................................................................................................... 98
5.3.1 Inhibition of Efflux Systems............................................................................. 98
5.3.2 Efflux Pump Inhibition to Improve Oral Bioavailability ................................. 99
5.3.2.1 Improving Oral Bioavailability by Using First-Generation Inhibitors... 99
5.3.2.2 Improving Oral Bioavailability by Using Second-and
Third-Generation Inhibitors .............................................................. 99
5.3.2.3 Improving Oral Bioavailability by Using Polymeric Agents .............. 99
5.3.3 Methods to Evaluate Efflux Pump Inhibition ................................................. 100
5.3.3.1 In Vitro Evaluation ........................................................................... 100
5.3.3.2 In Vivo Evaluation ............................................................................100
5.4 Conclusion and Future Trends .................................................................................. 100
References .......................................................................................................................... 101
Efflux systems and presystemic metabolism are, beside other reasons, responsible for low
bioavailability of orally administered drugs. Presystemic metabolism itself can be divided into
three subtypes: luminal metabolism, first-pass intestinal metabolism, and first-pass hepatic
metabolism. Luminal metabolism is caused mainly by secreted enzymes. Most important in
this context are proteases secreted from the pancreas such as trypsin and chymotrypsin,
esterases, and miscellaneous nucleases. For first-pass intestinal metabolism, brush border
membrane-bound enzymes including aminopeptidases and carboxypeptidases, as well as
intracellular occurring enzymes like esterases and above all CYP3A4 are responsible.
Absorbed drugs reach the liver through the portal circulation, where a certain amount of
administered drug is biotransformed before it reaches the systemic circulation. This is known
as the first-pass hepatic metabolism [1].
