Abstract
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 withKi 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 thesel-valyl esters showed higher affinity for rPEPT2 as do most substrates of these transporters. Our results suggest thatl-valine is a desirable l-amino acid for the esterification of poorly permeable drugs to enhance their oral bioavailability targeting intestinal PEPT1.
Footnotes
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Send reprint requests to: Prof. Ken-ichi Inui, Ph.D., Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: inui{at}kuhp.kyoto-u.ac.jp
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↵1 This work was supported in part by a Grant-in-Aid for Scientific Research (B) and a Grant-in-Aid for Scientific Research on Priority Areas of “Bio-molecular Design for Biotargeting” (11132235) from the Ministry of Education, Science, Sports, and Culture of Japan and by grants from the Uehara Memorial Foundation and from the Yamada Science Foundation.
- Abbreviations:
- PEPT
- peptide transporter
- rPEPT
- rat peptide transporter
- Val-OMe
- l-valine methyl ester
- Received May 27, 1999.
- Accepted August 5, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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