Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 43, Issue 20, Pages 3641-3652Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm980645y
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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. C-14-Labeled pamidronate and alendronate as well as radiolabeled and cold peptidyl-bisphosphonates, Pro-[H-3]Phe-[C-14]pamidronate, and Pro-[H-3]Phe-[C-14]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.
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