A Peptide Prodrug Approach for Improving Bisphosphonate Oral Absorption

• Published in: Journal of medicinal chemistry Vol. 43; no. 20; pp. 3641 - 3652
• Main Authors: Ezra, Aviva, Hoffman, Amnon, Breuer, Eli, Alferiev, Ivan S, Mönkkönen, Jukka, El Hanany-Rozen, Naama, Weiss, Gal, Stepensky, David, Gati, Irith, Cohen, Hagit, Törmälehto, Soili, Amidon, Gordon L, Golomb, Gershon
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.10.2000; Amer Chemical Soc
• Subjects: Administration, Oral; Alendronate - administration & dosage; Alendronate - analogs & derivatives; Alendronate - chemical synthesis; Alendronate - chemistry; Alendronate - pharmacokinetics; Animals; Biological and medical sciences; Biological Availability; Bones, joints and connective tissue. Antiinflammatory agents; Caco-2 Cells; Carrier Proteins - metabolism; Chemical Precipitation; Chemistry, Medicinal; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacokinetics; Diphosphonates - administration & dosage; Diphosphonates - chemical synthesis; Diphosphonates - chemistry; Diphosphonates - pharmacokinetics; Durapatite - chemistry; General pharmacology; Humans; Injections, Intravenous; Intestinal Absorption; Life Sciences & Biomedicine; Medical sciences; Pamidronate; Peptide Transporter 1; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Rats; Science & Technology; Symporters; Tissue Distribution; INTESTINAL-ABSORPTION; CONVERTING ENZYME; POSTMENOPAUSAL OSTEOPOROSIS; TRANSPORTER; CARRIER SYSTEM; PERMEABILITY; INVITRO; RATS; BETA-LACTAM ANTIBIOTICS; ALENDRONATE; Peptides; Rat; Biological transport; Rodentia; Gut; Oral administration; Diphosphonic acid derivatives; Drug carrier; Bioavailability; Prodrug; Bisphosphonates; Pamidronic acid; Alendronic acid; Vertebrata; Mammalia; Animal; Dipeptides; Absorption enhancer; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980645y

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.