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Vol. 291, Issue 2, 705-709, November 1999
Department of Pharmacy, Kyoto University Hospital, Faculty of
Medicine, Kyoto University, Kyoto, Japan
Peptide transporters (PEPT1 and PEPT2) in epithelia play an important
role in the absorption of small peptides and peptide-like drugs.
Recently, it was demonstrated that various nonpeptidic compounds can be
transported by these transporters. In the present study, we focused on
the L-amino acid ester compounds and examined the
mechanisms of their interaction with rat PEPTs (rPEPTs) using stable
transfectants. Valacyclovir, the L-valyl ester prodrug of
the antiherpetic agent acyclovir, competitively inhibited
[14C]glycylsarcosine uptake in the rPEPT1- or
rPEPT2-expressing cells. Dixon plot analyses showed that the inhibition
constant (Ki) values of valacyclovir were
2.7 and 0.22 mM for rPEPT1 and rPEPT2, respectively, suggesting that
rPEPT2 had higher affinity for this agent. Various L-valine
alkyl esters significantly inhibited [14C]glycylsarcosine
uptake. L-Valine methyl ester (Val-OMe) competitively inhibited [14C]glycylsarcosine uptake with
Ki values of 3.6 and 0.83 mM for rPEPT1 and
rPEPT2, respectively, indicating that Val-OMe is also a high-affinity
substrate for rPEPT2. Val-OMe had a trans-stimulation effect on [14C]glycylsarcosine efflux from both
transfectants, suggesting the translocation of L-valine
methyl ester via rPEPTs. Val-OMe showed the most potent inhibitory
effect among the several L-amino acid methyl esters
examined. We conclude that Val-OMe, as well as valacyclovir, could be
recognized and transported by rPEPT1 and rPEPT2 and that these
L-valyl esters showed higher affinity for rPEPT2 as
do most substrates of these transporters. Our results suggest that
L-valine is a desirable L-amino acid for the
esterification of poorly permeable drugs to enhance their oral
bioavailability targeting intestinal PEPT1.
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