Transepithelial transport of prodrugs of the HIV protease inhibitors saquinavir, indinavir, and nelfinavir across Caco-2 cell monolayers.
OBJECTIVE
[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.
Rouquayrol
Marielle
M
Laboratoire de Chimie Bioorganique, UMR 6001 CNRS, Université de Nice Sophia-Antipolis, Faculté des Sciences, Parc Valrose, 06108 Nice Cedex 2, France.
Gaucher
Bérangère
B
Roche
Dominique
D
Greiner
Jacques
J
Vierling
Pierre
P
D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000737:chemistry / Q000493:pharmacokinetics; D019888:Nelfinavir / Q000737:chemistry / Q000493:pharmacokinetics; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics*; D019258:Saquinavir / Q000737:chemistry / Q000493:pharmacokinetics
D017320:HIV Protease Inhibitors; D011355:Prodrugs; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir