Pharmacokinetics and anti-asthmatic potential of non-parenterally administered recombinant human interleukin-1 receptor antagonist in animal models.
The objectives of this study were to define the pharmacokinetics of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) and its effects on allergic asthma, cell adhesion molecules, and upper respiratory tract following non-parenteral administration in animals. Pharmacokinetics and immunomodulating effects of rhIL-1ra were investigated in Sprague-Dawley rats and asthmatic guinea pigs, respectively. Effects on the upper respiratory tract following the applications of rhIL-1ra were investigated on the ex vivo nasal mucosa of Sprague-Dawley rats and in situ in the upper palate of Chinese toads. Absolute bioavailabilities after intratracheal and intranasal administrations of rhIL-1ra were 94.3% and 24.8%, respectively. After administration of rhIL-1ra solution as ultrasonic spraying, the asthmatic symptom in guinea pigs was obviously attenuated. The plasma soluble intercellular cell adhesion molecule (sICAM-1) and P-selectin levels in asthmatic guinea pigs were each dose-dependently reduced with the increase of rhIL-1ra dose. The rhIL-1ra solution after administration via the airway seemed to have no impact on the integrity of nasal mucosa and mucocilia clearance in the upper respiratory tract. The present study provides evidence that rhIL-1ra effectively suppresses allergen-induced asthmatic symptoms through spraying, which corresponds to nasal and pulmonary absorption or both, and the efficacy is associated with downregulation of sICAM-1 and P-selectin expressions.
Li
Ting
T
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing, China.
Lu
Wan-Liang
WL
Hong
Hai-Yan
HY
Yao
Yan-Sheng
YS
Han
Pu
P
Li
Zhong-Kun
ZK
Wang
Gui-Ling
GL
Cao
Yi
Y
Liu
Xiang-Rui
XR
Wang
Jian-Cheng
JC
Zhang
Xuan
X
Zhang
Qiang
Q
D000281:Administration, Intranasal; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001682:Biological Availability; D002025:Bufonidae; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D006967:Hypersensitivity / Q000503:physiopathology; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D053590:Interleukin 1 Receptor Antagonist Protein / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D009079:Mucociliary Clearance / Q000502:physiology; D009297:Nasal Mucosa / Q000378:metabolism / Q000473:pathology; D010047:Ovalbumin / Q000276:immunology; D019007:P-Selectin / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects / Q000503:physiopathology
D018927:Anti-Asthmatic Agents; D015815:Cell Adhesion Molecules; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D019007:P-Selectin; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D010047:Ovalbumin