Abstract
Intestinal influx transporters are useful for the improvement of intestinal membrane permeability of drugs and/or pharmacologically active compounds under development. Peptide transporters PEPT1 accept various peptide-mimetics and transport them in a pH dependent manner. Three strategies to utilize PEPT1 are described, depending on the characteristics of the pharmacologically active compounds, including prodrug approaches and formulation technology. The first is for amino acid like compounds such as L-dopa. An addition of amino acid moiety to the pharmacologically active compound to be peptide mimetics is useful to be transported by PEPT1. The second is for peptide-like compounds which are not transported well by PEPT1. Cephalosporin antibiotic, cefixime, exhibited pH dependent transport via PEPT1 and the optimal pH to be transported by PEPT1 is more acidic than physiological intestinal luminal pH. In such case, acidification of intestinal lumen by acidic polymers such as Eudragit L100-55 can enhance PEPT1-mediated permeability without prodrug approach. The third is for non-amino acid or -peptide like compounds. Simple addition of peptide moiety to the pharmacologically active compounds is useful, since the attached peptide moiety could be accepted as substrate of PEPT1, while there is certain structural requirement for the modification to be accepted by PEPT1 well. The examples of those three strategies are described. Furthermore, organic anion transporting polypeptides OATPs such as OATP1A2 and OATP2B1 are likely involved as the intestinal absorptive transporters based on the effects of co-administered fruit juices and genetic polymorphisms of OATP2B1 on the absorption of OATP substrates in human as well as in vitro transport studies. Further characterization of intestinal OATPs should be essential to utilize them as the tools for the improvement of drug absorption.
