Synthesis of analogs of L-valacyclovir and determination of their substrate activity for the oligopeptide transporter in Caco-2 cells
In: European journal of pharmaceutical sciences, Jg. 16 (2002), Heft 1-2, S. 1-13
academicJournal
- print, 20 ref
Zugriff:
L-Valacyclovir, a prodrug of acyclovir, is a substrate for the peptide transporter (PepT1) in the intestinal mucosa, which accounts for its higher than expected oral bioavailability. The substrate activity of L-valacyclovir for PepT1 is surprising, particularly when one considers that the molecule has the structural features of a nucleoside rather than a peptide. In an attempt to better understand the structure-transport relationships (STR) for the interactions of L-valacyclovir with PepTl, analogs of this molecule with structural changes in the guanine moiety were synthesized and their substrate activity for PepT1 in Caco-2 cell monolayers was determined. The analogs synthesized include those that had the guanine moiety of L-valacyclovir substituted with purine, benzimidazole, and 7-azaindole. All three analogs (purine, benzimidazole, and 7-azaindole) exhibited affinity for PepT1 in binding studies, but only the purine analog (as the L-valine ester) showed PepTl-associated transcellular transport across Caco-2 cell monolayers. The benzimidazole and 7-azaindole analogs (as their L-valine esters) were rapidly metabolized by esterase when applied to the apical surface of Caco-2 cells, which probably explains their low penetration as the intact prodrugs via PepT1.
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Synthesis of analogs of L-valacyclovir and determination of their substrate activity for the oligopeptide transporter in Caco-2 cells
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Autor/in / Beteiligte Person: | FRIEDRICHSEN, Gerda Marie ; WEIQING, CHEN ; BEGTRUP, Mikael ; LEE, Chao-Pin ; SMITH, Philip L ; BORCHARDT, Ronald T |
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Zeitschrift: | European journal of pharmaceutical sciences, Jg. 16 (2002), Heft 1-2, S. 1-13 |
Veröffentlichung: | Shannon: Elsevier, 2002 |
Medientyp: | academicJournal |
Umfang: | print, 20 ref |
ISSN: | 0928-0987 (print) |
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