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  • Title: Transepithelial transport of prodrugs of the HIV protease inhibitors saquinavir, indinavir, and nelfinavir across Caco-2 cell monolayers.
    Author: Rouquayrol M, Gaucher B, Roche D, Greiner J, Vierling P.
    Journal: Pharm Res; 2002 Nov; 19(11):1704-12. PubMed ID: 12458677.
    Abstract:
    PURPOSE: [corrected] This study is dedicated to the permeation of various amino acid-, D-glucose-, and PEG-conjugates of indinavir, saquinavir, and nelfinavir across monolayers of Caco-2 cells as models of the intestinal barrier. This screening is aimed at detecting the most promising prodrugs for improving the intestinal absorption of these protease inhibitors. METHODS: The bidirectional transport of the prodrugs was investigated using P-gp-expressing Caco-2 monolayers grown on membrane inserts using high-performance liquid chromatography for quantitation. RESULTS: The L-valyl, L-leucyl, and L-phenylalanyl ester conjugates led to an enhancement of the absorptive flux of indinavir or saquinavir. These results are likely attributable to an active transport mechanism and/or to a decrease of their efflux by carriers such as P-gp. Connection of tyrosine through its hydroxyl, of D-glucose, or of polyethylene glycol decreased their absorptive and secretory diffusion. CONCLUSIONS: Conjugation of the protease inhibitors to amino acids constitutes a most appealing alternative that could improve their intestinal absorption and oral bioavailability. Whether it could improve their delivery into the central nervous system remains to be explored. D-Glucose conjugation will most probably not improve their intestinal absorption or their crossing of the blood-brain barrier. If some pharmacologic benefits are to be expected from PEG-protease inhibitor conjugates, they must then be administered intravenously.
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