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Selective Delivery of Estradiol to Bone by Aspartic Acid Oligopeptide and Its Effects on Ovariectomized Mice

Department of Hospital Pharmacy, School of Medicine (K.Y., K.-i.M.), Kanazawa University, Kanazawa 920-8641, Japan; Department of Clinical Pharmacy (K.Mi., T.S., Y.H., M.N.), Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan; Department of Biochemistry (R.F.), Faculty of Dentistry, Hokkaido University, Sapporo, Japan; Department of Microbiology (K.Mo., Y.M.), Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan; and Masticatory Function Control (Y.W., S.K.), Tokyo Medical and Dental University, Tokyo, Japan

Address all correspondence and requests for reprints to: Ken-ichi Miyamoto, Ph.D., Prof., Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13–1 Takara-machi, Kanazawa 920-8641, Japan. E-mail: miyaken{at}kenroku.ipc.kanazawa-u.ac.jp

We have developed a novel osteotropic prodrug of estradiol (E₂) conjugated with L-Asp-hexapeptide (E₂·3D₆), which has very low affinity for estrogen receptors, and in this study, we examined its pharmacokinetic behavior and pharmacological potential. After a single iv injection of E₂·3D₆ to mice, the half-time for elimination from plasma was about 100 min; however, E₂ was selectively delivered to the bone and eliminated very slowly, declining to the endogenous level at about 7 days. After a single iv injection of E₂, the half-time in plasma was about 70 min, whereas E₂ was highly distributed to the uterus, and the bone concentration of E₂ was only slightly increased at 6 h. When E₂ (0.37 µmol/kg, sc, every third day) or E₂·3D₆ (0.11 to 1.1 µmol/kg, sc, every seventh day) was administered to OVX mice for 4 weeks, E₂ increased the bone mineral density (BMD) together with weights of liver and uterus, whereas E₂·3D₆ increased only the BMD, in a dose-dependent manner. E₂·3D₆ enhanced the expression of messenger RNAs of bone matrix proteins (osteopontin, bone sialoprotein, type I collagen ) of OVX mice at 4 h after administration, but E₂ did very slightly. These results indicate that the E₂ prodrug was delivered to the bone, where it gradually released E₂, thereby ameliorating bone loss. This acidic oligopeptide appears to be a good candidate for selective drug delivery to bone.