Disposition of human recombinant lubricin in naive rats and in a rat model of post-traumatic arthritis after intra-articular or intravenous administration.
We have recently demonstrated that intra-articular (IA) administration of human recombinant lubricin, LUB:1, significantly inhibited cartilage degeneration and pain in the rat meniscal tear model of post-traumatic arthritis. In this report, we show that after a single IA injection to naïve rats and rats that underwent unilateral meniscal tear, [(125)I]LUB:1 had a tri-phasic disposition profile, with the alpha, beta, and gamma half-life estimates of 4.5 h, 1.5 days, and 2.1 weeks, respectively. We hypothesize that the terminal phase kinetics was related to [(125)I]LUB:1 binding to its ligands. [(125)I]LUB:1 was detected on articular cartilage surfaces as long as 28 days after single IA injection. Micro-autoradiography analysis suggested that [(125)I]LUB:1 tended to localize to damaged joint surfaces in rats with meniscal tear. After a single intravenous (IV) dose to rats, [(125)I]LUB:1 was eliminated rapidly from the systemic circulation, with a mean total body clearance of 154 mL/h/kg and a mean elimination half-life (t (1/2)) of 6.7 h. Overall, LUB:1 has met a desired disposition profile of a potential therapeutic intended for an IA administration: target tissue (knee) retention and fast elimination from the systemic circulation after a single IA or IV dose.
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, Pfizer Inc, Andover, Massachusetts, USA. yulia.vugmeyster@pfizer.com
Yulia
Y
Vugmeyster
Qin
Q
Wang
Xin
X
Xu
John
J
Harrold
Daren
D
Daugusta
Jian
J
Li
Richard
R
Zollner
Carl R
CR
Flannery
Moisés A
MA
Rivera-Bermúdez
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001345:Autoradiography / Q000379:methods; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007270:Injections, Intra-Articular; D007275:Injections, Intravenous; D007719:Knee Joint / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins; D013997:Time Factors; D014018:Tissue Distribution; D000099158:Proteoglycan 4
D006023:Glycoproteins; D011994:Recombinant Proteins; D000099158:Proteoglycan 4