Novel amphiphiles which carry many mannose residues as side chains were prepared by telomerization of N-methacryloylaminopropyl D-mannopyranoside (alpha:beta = 20:1), N-methacryloylaminohexyl D-mannopyranoside (alpha:beta = 20:1), or 3-(2-methacryloylaminoethylthio)propyl D-mannopyranoside (alpha:beta = 4:1) using a lipophilic radical initiator. The mannose-carrying amphiphiles incorporated in liposomes were recognized by a lectin from Canavalia ensiformis (Con A), which was proven by the increase in turbidity of the liposome suspension after mixing with Con A. The interaction between sugar residues on the liposome surface and the lectin was largely affected by the degree of polymerization (DP) and the surface density of the amphiphile in the liposomes. The distance between the sugar residues and the polymer main chain did not affect the specific recognition by the lectin significantly in the liposome system, whereas it appreciably affected the recognition in the water-soluble polymer system. The association constants (Ka) of the amphiphiles (DP approximately 18) with Con A (0.3-2.2 x 10(6) M-1 at 25 degrees C) were much larger than that of alpha-methyl D-mannopyranoside (8.2 x 10(3) M-1) due to the "cluster effect ". The positive entropy change (20-52 J/mol K) for the binding of Con A to mannose residues on the liposome surface showed that the recognition in the liposome system was largely promoted by the release of water molecules from both the sugar residues on the liposome surface and the binding site of Con A.
A lipid-polypeptide conjugate (lipo-polypeptide) was obtained by the ring-opening polycondensation of N-epsilon-Z-L-lysine N-carboxyanhydride (NCA) using 3-aminopropyl dioctadecylamine as initiator and subsequent deprotection. Maltose lactone was coupled with the lipo-polypeptide to give novel amphiphiles which carried many maltoamide residues as pendent groups. The sugar group-carrying amphiphiles incorporated in phospholipid liposomes were recognized by a lectin from Canavalia ensiformis (Con A), which was proven by the increase in turbidity of the liposome suspension after mixing with the lectin. The recognition was largely affected by the degree of polymerization of lysine residues and the surface density of the amphiphile in the liposomes. The association constant (K(ass)) of Con A with maltoamide residues on the liposome was much larger than those for small molecular weight sugars due to the "cluster effect".
-Purpose. This study aimed to develop a novel approach for predicting the oral absorption of low-solubility drugs by considering regional differences in solubility and permeability within the gastrointestinal (GI) tract. Methods. Simulated GI fluids were prepared to reflect rat in vivo bile acid and phospholipid concentrations in the upper and lower small intestine. The saturated solubility and permeability of griseofulvin (GF) and albendazole (AZ), a drug with low aqueous solubility, were measured using these simulated fluids, and fraction absorbed (Fa) at time t after oral administration was calculated. Results. The saturated solubility of GF and AZ, a drug with low aqueous solubility, differed considerably between the simulated GI fluids. Large regional differences in drugs concentration were also observed following oral administration in vivo. The predicted Fa values using solubility and permeability data of the simulated GI fluid were found to correspond closely to the in vivo data. Conclusion. These results indicated the importance of evaluating regional differences in drug solubility and permeability in order to predict oral absorption of low-solubility drugs accurately. The new methodology developed in the present study could be useful for new oral drug development.
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