A peptide prodrug approach for improving bisphosphonate oral absorption

A. Ezra, A. Hoffman, E. Breuer, I. S. Alferiev, J. Mönkkönen, N. El Hanany-Rozen, G. Weiss, D. Stepensky, I. Gati, H. Cohen, S. Törmälehto, G. L. Amidon, G. Golomb

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

This work was aimed at improving the absorption of bisphosphonates by targeting carrier systems in the intestine and the intestinal peptide carrier system (hPEPT1), in particular. 14C-Labeled pamidronate and alendronate as well as radiolabeled and 'cold' peptidyl-bisphosphonates, Pro-[3H]Phe-[14C]pamidronate, and Pro-[3H]Phe-[14C]alendronate were synthesized. In situ single-pass perfusion studies revealed competitive inhibition of transport by Pro-Phe, suggesting peptide carrier-mediated transport. Prodrug transport in the Caco-2 cell line was significantly better than that of the parent drugs, and the prodrugs exhibited high affinity to the intestinal tissue. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration in rats, and the bioavailability of Pro-Phe-alendronate was 3.3 (F(TIBIA)) and 1.9 (F(URINE)) times higher than that of the parent drug. The results indicate that the oral absorption of bisphosphonates can be improved by peptidyl prodrugs via the hPEPT1; however, other transporters may also be involved.

Original languageEnglish
Pages (from-to)3641-3652
Number of pages12
JournalJournal of Medicinal Chemistry
Volume43
Issue number20
DOIs
StatePublished - 5 Oct 2000
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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