Pharmaceutical and biological properties of doxorubicin encapsulated in liposomes (L-ADM): the effect of repeated administration on the systemic phagocytic activity and pharmacokinetics.
We investigated the biodistribution and antitumour activity of doxorubicin (ADM) encapsulated in liposomes (L-ADM) after two administrations in tumour bearing mice. The effect of the first administration on phagocytic activity was also examined. The biodistribution of L-ADM after the second dosing at an interval of 4d was remarkably different from that after the first. The concentration of ADM in plasma and tumour after the second injection was higher, but that in the liver was lower than after the first administration. This decrease in distribution to the liver is thought to have contributed to the difference in the biodistribution characteristics of L-ADM. With regard to antitumour effect, the activity was similar between L-ADM and a solution of ADM (F-ADM). To investigate the effect of the first administration of L-ADM on biodistribution, systemic phagocytic activity was measured after the injection of F-ADM, L-ADM, or 'empty' liposomes not containing ADM. F-ADM and L-ADM (7.5 mg ADM/kg body weight) reduced phagocytic activity to approximately 50% and 30% of control, respectively. This finding suggests that entrapment of ADM in liposomes enhances both the distribution of the drug to the reticuloendothelial system (RES) and its suppressive effect on RES activity. These results indicate that the decrease in RES activity by L-ADM must be considered in estimation of the pharmacokinetics, antitumour activity, and toxicity of L-ADM in clinical use when given by repeat administration or used in combination with other antitumour agents.
Yachi
K
K
Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Kikuchi
H
H
Suzuki
N
N
Atsumi
R
R
Aonuma
M
M
Kawato
Y
Y
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers; D004339:Drug Compounding; D008081:Liposomes; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010316:Particle Size; D010587:Phagocytosis / Q000187:drug effects*; D012156:Reticulocytes / Q000187:drug effects; D014018:Tissue Distribution / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin