Effect of poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) micelles on pharmacokinetics and intestinal toxicity of irinotecan hydrochloride: potential involvement of breast cancer resistance protein (ABCG2).
OBJECTIVE
Intestinal toxicity and low levels of systemic drug exposure are among the major problems associated with tumour therapy. We have developed poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) (PEO-PPO-PEO) micelles loaded with irinotecan hydrochloride (CPT-11) hoping to decrease CPT-11-induced intestinal toxicity while increasing its systemic exposure. In addition, we have investigated the potential involvement of breast cancer resistance protein (BCRP) in biliary excretion, pharmacokinetics, and intestinal toxicity of CPT-11.


METHODS
PEO-PPO-PEO micelles were prepared using PEO(20)-PPO(70)-PEO(20) and lecithin. The effect of PEO-PPO-PEO micelles on BCRP-mediated cellular accumulation and transport efflux of CPT-11 was evaluated in MDCKII/BCRP cells. The biliary excretion, intestinal damage, and pharmacokinetic study of CPT-11-loaded PEO-PPO-PEO micelles were investigated in rats.


RESULTS
The obtained micelles could effectively inhibit BCRP-mediated CPT-11 efflux in MDCKII/BCRP cells, and significantly decrease the drug biliary excretion in rats. Moreover, intestinal toxicity, assessed by microscopic examination of pathological damage, was ameliorated in rats injected with PEO-PPO-PEO micelles compared with rats injected with CPT-11 alone. Treatment with PEO-PPO-PEO micelles resulted in prolonged circulation time in blood and increased bioavailability of CPT-11 and SN-38 (7-ethyl-10-hydroxycamptothecin).


CONCLUSIONS
PEO-PPO-PEO micelles were identified as promising carriers able to reduce intestinal toxicity and increase antitumour therapeutic effect of CPT-11. The study indicated a potential involvement of BCRP in CPT-11 pharmacokinetics and CPT-11-induced intestinal toxicity.
Guo
Shiyan
S
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, PR China.
Zhang
Xinxin
X
Gan
Li
L
Zhu
Chunliu
C
Gan
Yong
Y
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D001692:Biological Transport; D001711:Biotransformation; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D004337:Drug Carriers; D004339:Drug Compounding; D004847:Epithelial Cells / Q000378:metabolism; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D000077146:Irinotecan; D054709:Lecithins / Q000737:chemistry; D008297:Male; D008823:Micelles; D009675:Novobiocin / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D011409:Propylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D054709:Lecithins; D008823:Micelles; C116176:PEO-PPO-PEO; D011409:Propylene Glycols; D009675:Novobiocin; D011092:Polyethylene Glycols; D000077146:Irinotecan; D002166:Camptothecin