Inhibitory effect of sulfobutyl ether β-cyclodextrin on DY-9760e-induced cellular damage: In vitro and in vivo studies
Yukihiko Nagase1, Hidetoshi Arima2, Koki Wada2, Tadaki Sugawara3, Hiroshi Satoh3, Fumitoshi Hirayama2, Kaneto Uekama2 *
1Analytical Research Center, Chemical Technology Research Laboratories, Daiichi Pharmaceutical Co. Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan
2Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
3Drug Safety Research Laboratory, Daiichi Pharmaceutical Co. Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan
email: Kaneto Uekama (uekama@gpo.kumamoto-u.ac.jp)
*Correspondence to Kaneto Uekama, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. Telephone: 81-96-371-4160; Fax: 81-96-371-4420
Abstract
The effects of water-soluble β-cyclodextrin derivatives (β-CyDs), such as 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) and sulfobutyl ether β-cyclodextrin (SBE7-β-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 β-CyDs SBE7-β-CyD forms the most stable inclusion complex in phosphate-buffered saline, probably because of a synergetic effect of hydrophobic and electrostatic interactions. β-CyDs inhibited DY-9760e-induced cell death toward HUVECs in an order of G2-β-CyD < β-CyD < HP-β-CyD < SBE7-β-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-β-CyD suppressed a DY-9760e-induced irritation such as thrombus, desquamation of the endothelium vasculitis, and perivasculitis. The present data indicated that SBE7-β-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-β-CyD as a parenteral carrier for DY-9760e. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2466-2474, 2003