title: Selective delivery of estradiol to bone by aspartic acid oligopeptide and its effects on ovariectomized mice.
abstract: We have developed a novel osteotropic prodrug of estradiol (E(2)) conjugated with L-Asp-hexapeptide (E(2).3D(6)), 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 E(2) x 3D(6) to mice, the half-time for elimination from plasma was about 100 min; however, E(2) 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 E(2), the half-time in plasma was about 70 min, whereas E(2) was highly distributed to the uterus, and the bone concentration of E(2) was only slightly increased at 6 h. When E(2) (0.37 micromol/kg, sc, every third day) or E(2) x 3D(6) (0.11 to 1.1 micromol/kg, sc, every seventh day) was administered to OVX mice for 4 weeks, E(2) increased the bone mineral density (BMD) together with weights of liver and uterus, whereas E(2) x 3D(6) increased only the BMD, in a dose-dependent manner. E(2) x 3D(6) enhanced the expression of messenger RNAs of bone matrix proteins (osteopontin, bone sialoprotein, type I collagen alpha) of OVX mice at 4 h after administration, but E(2) did very slightly. These results indicate that the E(2) prodrug was delivered to the bone, where it gradually released E(2), thereby ameliorating bone loss. This acidic oligopeptide appears to be a good candidate for selective drug delivery to bone.
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yokogawa
authors.forename: K
authors.initials: K
authors.lastname: Miya
authors.forename: T
authors.initials: T
authors.lastname: Sekido
authors.forename: Y
authors.initials: Y
authors.lastname: Higashi
authors.forename: M
authors.initials: M
authors.lastname: Nomura
authors.forename: R
authors.initials: R
authors.lastname: Fujisawa
authors.forename: K
authors.initials: K
authors.lastname: Morito
authors.forename: Y
authors.initials: Y
authors.lastname: Masamune
authors.forename: Y
authors.initials: Y
authors.lastname: Waki
authors.forename: S
authors.initials: S
authors.lastname: Kasugai
authors.forename: K
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives; D001857:Bone Matrix / Q000737:chemistry; D001842:Bone and Bones / Q000187:drug effects*; D004958:Estradiol / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology*; D004966:Estrogens, Conjugated (USP) / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D051379:Mice; D010052:Ovariectomy; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D004966:Estrogens, Conjugated (USP); D011355:Prodrugs; D011506:Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C423369:estradiol (E(2))-Asp-hexapeptide conjugate; D001224:Aspartic Acid; D004958:Estradiol