Route of administration-dependent anti-inflammatory effect of liposomal alendronate.
Innate immunity and inflammation are of major importance in various pathological conditions. Intravenous (IV) and intraperitoneal (IP) liposomal alendronate (LA) treatments have been shown to deplete circulating monocytes and peritoneal macrophages resulting in the inhibition of restenosis and endometriosis (EM), respectively. Nevertheless, the correlation between the extent of circulating monocyte depletion and liposome biodistribution is unknown, and the route of administration-dependent bioactivity in restenosis and EM has not been determined. We found that, LA treatment resulted in a dose-response modified biodistribution following both IV and IP administrations. The biodistribution of high-dose LA (10mg/kg), but not that of the low-dose (1mg/kg), was similar in healthy and diseased animals. It is concluded that LA impedes its own elimination from the circulation by depleting circulating monocytes and/or inhibiting their endocytic activity, in a dose-dependent manner. Both IV and IP administration of LA mediated by the partial and transient depletion of circulating monocytes effected inhibition of restenosis. Inhibition of EM was effected only by IP administration, which depleted both intraperitoneal and circulating monocytes. Thus, EM should be considered as a local inflammatory condition with systemic manifestations as opposed to restenosis, a systemic inflammatory disease.
Haber
E
E
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
Afergan
E
E
Epstein
H
H
Gutman
D
D
Koroukhov
N
N
Ben-David
M
M
Schachter
M
M
Golomb
G
G
D019386:Alendronate / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D016893:Carotid Stenosis / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004715:Endometriosis / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D011817:Rabbits; D051381:Rats; D014018:Tissue Distribution
D000893:Anti-Inflammatory Agents; D008081:Liposomes; D019386:Alendronate