Add time:08/13/2019         Source:sciencedirect.com

The oligopeptide transporter, which contributes to the absorption of di-/tri-peptides and various peptidomimetic compounds across intestinal epithelia, is expressed in mature Caco-2 monolayers. It was shown in our previous report that β-esterified d-Asp(OBzl)-Ala is efficiently transported across Caco-2 monolayers via the oligopeptide transporter (Taub et al., Int. J. Pharmaceutics 146, 1997b, 205–212). In this paper we demonstrate that two additional peptidase resistant side-chain modified dipeptides, d-Glu(OBzl)-Ala and d-Ser(Bzl)-Ala, are also substrates for the Caco-2 oligopeptide transporter. These three modified dipeptides, chosen due to their sequential difference in number of CH2 groups in the side-chain, demonstrate different affinity (IC50) and apparent permeability (Papp) values, uptake profiles, and pH-mediated release of the benzyl group. Both uptake and transport of d-Asp(OBzl)-Ala, d-Glu(OBzl)-Ala, and d-Ser(Bzl)-Ala in Caco-2 monolayers are >90% inhibitable by the presence of a 20-fold molar excess of Gly-Pro in the apical chamber. The Papp of d-Asp(OBzl)-Ala is nearly 2-fold greater than that of d-Glu(OBzl)-Ala and 4-fold greater that that of d-Ser(Bzl)-Ala. The half-life (t1/2) for the release of benzyl alcohol (BZ-OH) from each dipeptide is also variable; d-Asp(OBzl)-Ala is labile at pH 6.0 and 7.4 (t1/2=26.1 and 7.8 h, respectively), while d-Glu(OBzl)-Ala is extremely stable at pH 6.0 but unstable at pH 7.4 (t1/2>96 and 2.1 h, respectively). d-Ser(Bzl)-Ala, which has a hydrolysis resistant ether linkage rather than a hydrolysis sensitive ester-linked benzyl group, is highly stable (t1/2>96 h at both pH 6.0 and 7.4). These data indicate that it is possible to construct various side-chain modified, peptidase resistant dipeptides having not only different oligopeptide transporter mediated permeability profiles, but also different release characteristics for the attached side-chain moiety.

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