PEGylation of osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF) results in decreased uptake into rats and human liver.
OBJECTIVE
Our aim was to investigate the effect of PEGylation on the uptake of osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF) into rat liver, kidney and spleen, and human liver.


METHODS
Copolymer of polyethyleneglycol allylmethylether and maleamic acid sodium salt with OCIF (poly(PEG)-OCIF) (0.5 mg/kg) was administered to rats and the concentrations of poly(PEG)-OCIF in the liver, kidney and spleen at 15 min after administration were measured by ELISA. For human liver uptake, the liver perfusion of OCIF and (3)H-labelled poly(PEG)-OCIF was conducted using fresh human liver block.


RESULTS
The tissue uptake of poly(PEG)-OCIF in rats was significantly lower compared with that of OCIF. In fresh human liver perfusion, (3)H-poly(PEG)-OCIF was rarely taken up into the liver. On the other hand, more than 50% of the perfused OCIF was taken up.


CONCLUSIONS
PEGylation of OCIF using poly(PEG) dramatically suppressed the uptake of OCIF into human liver as well as into rat liver and could be a promising approach for improving the pharmacokinetic and pharmacological effects of OCIF in the clinical setting.
Saito-Yabe
Motoko
M
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. saito.motoko.zf@daiichisankyo.co.jp
Kasuya
Yuji
Y
Yoshigae
Yasushi
Y
Yamamura
Naotoshi
N
Suzuki
Yukie
Y
Fukuda
Nao
N
Honma
Masashi
M
Yano
Kazuki
K
Mochizuki
Shin-Ichi
S
Okada
Fumihiko
F
Okada
Akiko
A
Nagayama
Yuki
Y
Tsuda
Eisuke
E
Fischer
Thomas
T
Höpner
Ursula
U
Zaja
Silvia
S
Mueller
Juergen
J
Okada
Junichi
J
Kurihara
Atsushi
A
Ikeda
Toshihiko
T
Okazaki
Osamu
O
D000818:Animals; D001692:Biological Transport; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006493:Heparin / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008298:Maleates / Q000737:chemistry; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects; D053244:Osteoprotegerin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D010052:Ovariectomy; D010477:Perfusion; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
D050071:Bone Density Conservation Agents; D008298:Maleates; D053244:Osteoprotegerin; D011092:Polyethylene Glycols; D006493:Heparin; C008311:maleamic acid