title: A peptide prodrug approach for improving bisphosphonate oral absorption.
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. (14)C-Labeled pamidronate and alendronate as well as radiolabeled and "cold" peptidyl-bisphosphonates, Pro-[(3)H]Phe-[(14)C]pamidronate, and Pro-[(3)H]Phe-[(14)C]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.
authors.affiliation: Department of Pharmaceutics and Medicinal Chemistry, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P. O. Box 12065, Jerusalem 91120, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Ezra
authors.forename: A
authors.initials: A
authors.lastname: Hoffman
authors.forename: E
authors.initials: E
authors.lastname: Breuer
authors.forename: I S
authors.initials: IS
authors.lastname: Alferiev
authors.forename: J
authors.initials: J
authors.lastname: Mönkkönen
authors.forename: N
authors.initials: N
authors.lastname: El Hanany-Rozen
authors.forename: G
authors.initials: G
authors.lastname: Weiss
authors.forename: D
authors.initials: D
authors.lastname: Stepensky
authors.forename: I
authors.initials: I
authors.lastname: Gati
authors.forename: H
authors.initials: H
authors.lastname: Cohen
authors.forename: S
authors.initials: S
authors.lastname: Törmälehto
authors.forename: G L
authors.initials: GL
authors.lastname: Amidon
authors.forename: G
authors.initials: G
authors.lastname: Golomb
mesh_terms: D000284:Administration, Oral; D019386:Alendronate / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism; D011232:Chemical Precipitation; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004164:Diphosphonates / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017886:Durapatite / Q000737:chemistry; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D000077268:Pamidronate; D000074011:Peptide Transporter 1; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D027981:Symporters; D014018:Tissue Distribution
chemical_list: D002352:Carrier Proteins; D004151:Dipeptides; D004164:Diphosphonates; D000074011:Peptide Transporter 1; D011355:Prodrugs; C082186:SLC15A1 protein, human; C489940:Slc15a1 protein, rat; D027981:Symporters; C415155:prolyl-phenylalanyl-alendronate; C415154:prolyl-phenylalanyl-pamidronate; D017886:Durapatite; D000077268:Pamidronate; D019386:Alendronate