Pharmacokinetics and disposition of recombinant human osteoprotegerin (rhOPG) after intravenous administration in female fischer rats.
1. Osteoprotegerin (OPG) is a secreted member of the tumour necrosis factor receptor (TNFR) family that leads to the suppression of the differentiation, activation and survival of osteoclasts. The objective was to investigate the in vivo pharmacokinetics and tissue distribution of full-length recombinant human OPG (rhOPG) as well as its clearance mechanism using (125)I-labelled protein ((125)I-rhOPG) after intravenous administration to female Fischer rats. 2. (125)I-rhOPG was rapidly and predominantly distributed to the liver after dosing (3 mg kg(-1)). Immunohistochemical analysis indicated that rhOPG was located in the sinusoids of the liver. 3. The hepatic uptake of (125)I-rhOPG (0.01 mg kg(-1)) was partly regulated under a saturable process. Pre-dosing of some sulfated glycans (20 mg kg(-1)), especially dextran sulfate, heparin and fucoidan, markedly inhibited the hepatic uptake of (125)I-rhOPG. The clearance of (125)I-rhOPG was markedly reduced by the conjugation of dextran sulfate. 4. The results suggested that the hepatic clearance of (125)I-rhOPG was mainly mediated by the interaction with glycosaminoglycans.
Miyaji
Y
Y
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co., Ltd., Tokyo, Japan. miyaji.yoshihiro.kc@daiichisankyo.co.jp
Kurihara
A
A
Kamiyama
E
E
Shiiki
T
T
Kawai
K
K
Okazaki
O
O
D000818:Animals; D001345:Autoradiography; D016264:Dextran Sulfate / Q000494:pharmacology; D005260:Female; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D053244:Osteoprotegerin / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*; D011134:Polysaccharides / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics*
D053244:Osteoprotegerin; D011134:Polysaccharides; D011994:Recombinant Proteins; D006493:Heparin; D016264:Dextran Sulfate; C007789:fucoidan