Pharmacokinetic and pharmacological profiles of free and liposomal recombinant human erythropoietin after intravenous and subcutaneous administrations in rats.
OBJECTIVE
Recombinant human erythropoietin (Epo) is used frequently through intravenous (i.v.) and subcutaneous (s.c.) administration for the clinical treatment of the last stage of renal anemia. We encapsulated Epo in liposomes to develop an alternative administration route. The purpose of our study was to evaluate the pharmacokinetics and the pharmacological effects of liposomal Epo in comparison with the Epo after i.v. and s.c. administration to rats.


METHODS
Epo was encapsulated in liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and soybean-derived sterol mixture (SS) prepared by the reversed-phase evaporation vesicle method. After filtration through a 0.1 micron polycarbonate membrane, liposomes were gel filtered (Epo/liposomes).


RESULTS
Epo/liposomes showed higher pharmacological activity than Epo/liposomes before gel filtration after i.v. administration to rats. Non-encapsulated Epo lost its activity, whereas encapsulated Epo in liposomes retained it. The pharmacological effects of Epo/liposomes were greater than those of Epo after i.v. administration. Epo/liposomes afforded 3-9 times higher AUC, lower clearance and lower steady-state volume of distribution than Epo after both i.v. and s.c. administrations. Epo/liposomes had an improved pharmacokinetics profile compared with Epo. S.c. administration of Epo/liposomes at 7 h may penetrate primarily (40% of dose) through the blood as a liposome and partly (7% of dose) in lymph. CONCLUSIONS. Epo/liposomes may reduce the frequency of injections required for a certain reticulocyte effect in comparison to Epo. The lower clearance of Epo/liposomes may increase the plasma concentrations of Epo, which increases the efficacy.
Moriya
H
H
Department of Pharmaceutics, Hoshi University, Tokyo, Japan.
Maitani
Y
Y
Shimoda
N
N
Takayama
K
K
Nagai
T
T
D000818:Animals; D004921:Erythropoietin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008081:Liposomes / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008196:Lymph / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012156:Reticulocytes / Q000378:metabolism
D008081:Liposomes; D004921:Erythropoietin