title: Development of polyethylene glycol-conjugated alendronate, a novel nitrogen-containing bisphosphonate derivative: evaluation of absorption, safety, and effects after intrapulmonary administration in rats.
abstract: Bisphosphonates are widely used for the treatment of bone diseases, including hypercalcemia and osteoporosis. However, the bioavailability (BA) of orally administered bisphosphonates is low, at approximately 0.9%-1.8%. In addition, the oral administration of bisphosphonates is associated with mucosal damage, including gastritis, gastric ulcer, and erosive esophagitis. Here, to develop a new delivery system for bisphosphonates that improve their BA and safety, we developed polyethylene glycol (PEG)-conjugated alendronate, a novel nitrogen-containing bisphosphonate derivative. We evaluated the absorption and safety of PEG-alendronate in rats following intrapulmonary administration. The BA of PEG-alendronate after intrapulmonary administration was approximately 44 ± 10% in rats, which was similar to that of alendronate (54 ± 3.9%). Alendronate significantly increased total protein concentration and lactate dehydrogenase activity in bronchoalveolar lavage fluid, suggesting that pulmonary epithelium was locally damaged by intrapulmonary administration of alendronate. In marked contrast, PEG-alendronate did not significantly increase the markers following intrapulmonary administration. In an osteoporosis model in rats, intrapulmonary administration of PEG-alendronate effectively inhibited decreases in the width of the growth plate to a level similar to that achieved by intrapulmonary administration of alendronate. These results indicate that pulmonary delivery of PEG-alendronate is a promising approach for the treatment of bone diseases.
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.forename: Miki
authors.initials: M
authors.lastname: Takashima
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sano
authors.forename: Kazushi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Noriko
authors.initials: N
authors.lastname: Kitamura
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sakane
authors.forename: Toru
authors.initials: T
authors.lastname: Hibi
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D019386:Alendronate / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D004333:Drug Administration Routes; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D050071:Bone Density Conservation Agents; D011092:Polyethylene Glycols; D007770:L-Lactate Dehydrogenase; D019386:Alendronate