title: Absorption and safety of alendronate, a nitrogen-containing bisphosphonate, after intrapulmonary administration in rats.
abstract: Alendronate, a nitrogen-containing bisphosphonate, has been used as a first-choice drug for the treatment of hypercalcemia and osteoporosis. In the present study, we examined the absorption and safety of alendronate after intrapulmonary administration in rats. The bioavailability (BA) of alendronate after intrapulmonary administration was 47% at a dose of 5 mg/kg, while the BA after oral administration was only 2.9% at a dose of 50 mg/kg in rats. Plasma calcium level, an index of the pharmacological effect of alendronate, was effectively reduced after intrapulmonary administration of alendronate. Furthermore, alendronate continuously reduced the increase in plasma calcium levels for 9 days after a single intrapulmonary administration in rats with 1α-hydroxyvitamin-D(3)-induced hypercalcemia. Intrapulmonary administration of alendronate also effectively suppressed the decrease in bone mass in a rat model of osteoporosis. Alendronate significantly increased the activity of lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF), indicating that pulmonary mucosal damage was induced by intrapulmonary administration of alendronate. However, co-administration of superoxide dismutase (SOD) with alendronate completely suppressed the alendronate-induced increase in LDH activity in BALF, while maintaining sufficient pulmonary absorption and therapeutic effects of alendronate in rats with 1α-hydroxyvitamin-D(3)-induced hypercalcemia. These findings indicated that the lung is a promising, noninvasive alternative route for the delivery of alendronate in the treatment of bone diseases.
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.forename: Maria
authors.initials: M
authors.lastname: Nakatani
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sano
authors.forename: Mari
authors.initials: M
authors.lastname: Abe
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kusamori
authors.forename: Maki
authors.initials: M
authors.lastname: Kurihara
authors.forename: Rika
authors.initials: R
authors.lastname: Shiota
authors.forename: Miki
authors.initials: M
authors.lastname: Takashima
authors.forename: Takuya
authors.initials: T
authors.lastname: Fujita
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 / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002118:Calcium / Q000097:blood; D016503:Drug Delivery Systems; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D050071:Bone Density Conservation Agents; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D002118:Calcium; D019386:Alendronate