Absorption and safety of alendronate, a nitrogen-containing bisphosphonate, after intrapulmonary administration in rats.
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.
Katsumi
Hidemasa
H
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Nakatani
Maria
M
Sano
Jun-ichi
J
Abe
Mari
M
Kusamori
Kosuke
K
Kurihara
Maki
M
Shiota
Rika
R
Takashima
Miki
M
Fujita
Takuya
T
Sakane
Toshiyasu
T
Hibi
Toru
T
Yamamoto
Akira
A
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
D050071:Bone Density Conservation Agents; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D002118:Calcium; D019386:Alendronate