Pharmacokinetic and therapeutic efficacy of intrapulmonary administration of zoledronate for the prevention of bone destruction in rheumatoid arthritis.
Zoledronate, a third-generation nitrogen-containing bisphosphonate, is a new therapeutic agent for the prevention of joint destruction in rheumatoid arthritis (RA). Due to the poor oral absorption of zoledronate, the intravenous route has been the preferred method of administration. To evaluate whether the lung is a promising alternative route of zoledronate administration for the prevention of joint destruction in RA, we examined the pharmacokinetics, safety and therapeutic potential of zoledronate after intrapulmonary administration. The bioavailability of zoledronate was 55% after intrapulmonary administration in rats. In a collagen-induced RA mouse model, an intrapulmonary administration of zoledronate given 7 d before the 2nd collagen immunization effectively suppressed bone loss and joint destruction to a level similar to that achieved with intravenous injection at 21 d after the 2nd collagen immunization. Zoledronate only slightly affected lactate dehydrogenase activity in bronchoalveolar lavage fluid 4 h after intrapulmonary administration of the therapeutic dose in rats. Moreover, zoledronate only slightly changed the plasma level of creatinine after intrapulmonary administration while creatinine significantly increased after intravenous injection of zoledronate in mice. These results indicate that the lung is a promising alternative route of zoledronate administration for the treatment and prevention of joint destruction in RA.
a Department of Biopharmaceutics and.
Hidemasa
H
Katsumi
a Department of Biopharmaceutics and.
Takunori
T
Mozume
a Department of Biopharmaceutics and.
Shin-Ichiro
S
Yanagi
b Department of Public Health , Kyoto Pharmaceutical University , Kyoto , Japan.
Tomohiro
T
Hasei
b Department of Public Health , Kyoto Pharmaceutical University , Kyoto , Japan.
Tetsushi
T
Watanabe
a Department of Biopharmaceutics and.
Toshiyasu
T
Sakane
a Department of Biopharmaceutics and.
Akira
A
Yamamoto
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000473:pathology; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003094:Collagen / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D004164:Diphosphonates / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D051381:Rats; D017208:Rats, Wistar; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D003094:Collagen; D003404:Creatinine
Bisphosphonate; drug delivery; pharmacodynamic activity; pulmonary delivery; rheumatoid arthritis; zoledronate