Inhibitory effect of sulfobutyl ether beta-cyclodextrin on DY-9760e-induced cellular damage: In vitro and in vivo studies.
The effects of water-soluble beta-cyclodextrin derivatives (beta-CyDs), such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and sulfobutyl ether beta-cyclodextrin (SBE7-beta-CyD) on cytotoxicity of DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) toward human umbilical vein endothelial cells (HUVECs) in vitro and vascular damage of the auricular vein of rabbits by DY-9760e in vivo were investigated. The spectroscopic study revealed that of the four beta-CyDs SBE7-beta-CyD forms the most stable inclusion complex in phosphate-buffered saline, probably because of a synergetic effect of hydrophobic and electrostatic interactions. beta-CyDs inhibited DY-9760e-induced cell death toward HUVECs in an order of G(2)-beta-CyD < beta-CyD < HP-beta-CyD < SBE7-beta-CyD, which was consistent with the order of the magnitude of stability constants. When the DY-9760e solution was infused into the auricular vein of rabbits for 24 h, SBE7-beta-CyD suppressed a DY-9760e-induced irritation such as thrombus, desquamation of the endothelium vasculitis, and perivasculitis. The present data indicated that SBE7-beta-CyD formed an inclusion complex with DY-9760e in a buffer solution and possessed the protective effect on DY-9760e-induced cytotoxicity toward HUVECs and vascular damage in rabbits. These results suggested potential use of SBE7-beta-CyD as a parenteral carrier for DY-9760e.
Nagase
Yukihiko
Y
Analytical Research Center, Chemical Technology Research Laboratories, Daiichi Pharmaceutical Co. Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Arima
Hidetoshi
H
Wada
Koki
K
Sugawara
Tadaki
T
Satoh
Hiroshi
H
Hirayama
Fumitoshi
F
Uekama
Kaneto
K
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003505:Cyclodextrins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004423:Ear / Q000098:blood supply; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D006801:Humans; D007191:Indazoles / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D011817:Rabbits; D013816:Thermodynamics; D014680:Veins / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D047392:beta-Cyclodextrins
C109602:3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate; D003505:Cyclodextrins; D007191:Indazoles; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin