Distribution characteristics of entrapped recombinant human erythropoietin in liposomes and its intestinal absorption in rats.
Recombinant human erythropoietin (Epo) is frequently administered by intravenous (i.v.) injection for the clinical treatment of renal anemia. Oral (per os; p.o.) administration is desired as an alternative route to i.v. administration, and liposomes have been chosen as a drug carrier. We found previously that after a p.o. administration to rats of Epo entrapped in liposomes before gel filtration, the Epo was absorbed, but variability in the number of days of appearance and in the levels of pharmacological effects, i.e. , the peak of circulating reticulocyte counts (RTC), was observed. The purpose of the present study was to examine the distribution characteristics of Epo in liposomes and intestinal absorption of liposomal Epo in rats by using purified Epo entrapped in liposomes after gel filtration (Epo/liposomes). The distribution characteristics of Epo/liposomes were determined by measuring the Epo in liposomes by a radioimmunoassay, high-performance liquid chromatography and zeta potential measurements. We observed that the protein part of Epo was mostly entrapped in liposomes, and was not adsorbed by the liposomal membrane at middle and high Epo p.o. doses, but the zeta potential of the Epo/liposomes increased negatively with the increase in the Epo p.o. doses. These results suggest that the sialic acid part of Epo entrapped in liposomes may project out from liposomes, depending on the entrapped Epo concentration. Little Epo was adsorbed or penetrated into liposomes when it was added to empty liposomes. After the p. o. administration of Epo/liposomes, the peak of RTC appeared at a 2-day delay on day 6, without variation and without dose dependency in comparison with that after i.v. administration. These results suggest that one of the reasons for the variability may be because the non-entrapped Epo and/or Epo/liposomes itself affected the intestinal absorption of Epo/liposomes. In conclusion, Epo/liposomes without nonentrapped Epo may be clinically useful for the oral administration of Epo.
Maitani
Y
Y
Department of Pharmaceutics, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan. yoshie@hoshi.ac.jp
Moriya
H
H
Shimoda
N
N
Takayama
K
K
Nagai
T
T
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004921:Erythropoietin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008081:Liposomes; D008297:Male; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D017701:Reticulocyte Count / Q000187:drug effects
D004337:Drug Carriers; D008081:Liposomes; D011994:Recombinant Proteins; D004921:Erythropoietin