Oligopeptide transporter mediated uptake and transport of D-Asp(OBzl)-Ala, D-Glu(OBzl)-Ala, and D-Ser(Bzl)-Ala in filter-grown Caco-2 monolayers

被引:18
作者
Taub, ME
Moss, BA
Steffansen, B
Frokjaer, S
机构
[1] Royal Danish Sch Pharm, Dept Pharmaceut, DK-2100 Copenhagen 0, Denmark
[2] PolyPeptide Labs, DK-3400 Hillerod, Denmark
关键词
Caco-2; dipeptide; oligopeptide transporter; transport; uptake;
D O I
10.1016/S0378-5173(98)00270-1
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 beta-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 CH, groups in the side-chain, demonstrate different affinity (IC50) and apparent permeability (P-app) values, uptake profiles, and pH-mediated release of the benzyl group. Both uptake and transport of D-Asp(OBzI)-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 P-app 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 (t(1/2)) 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 (t(1/2) = 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 (t(1/2) > 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 (t(1/2) > 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. (C) 1998 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:223 / 232
页数:10
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