Yokogawa K, Miya K, Sekido T, Higashi Y, Nomura M, Fujisawa R, Morito K, Masamune Y, Waki Y, Kasugai S, Miyamoto K
Department of Hospital Pharmacy, School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan.
Endocrinology. 2001 Mar;142(3):1228-33. doi: 10.1210/endo.142.3.8024.
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.
我们研发了一种新型的雌二醇（E₂）骨靶向前药，它与L-天冬氨酸六肽（E₂.3D₆）偶联，对雌激素受体的亲和力非常低。在本研究中，我们检测了其药代动力学行为和药理潜力。给小鼠单次静脉注射E₂×3D₆后，血浆消除半衰期约为100分钟；然而，E₂被选择性地输送到骨骼且消除非常缓慢，约7天后降至内源性水平。单次静脉注射E₂后，血浆半衰期约为70分钟，而E₂高度分布于子宫，6小时时骨骼中E₂浓度仅略有增加。当给去卵巢（OVX）小鼠每隔三天皮下注射E₂（0.37微摩尔/千克）或每隔七天皮下注射E₂×3D₆（0.11至1.1微摩尔/千克），持续4周时，E₂增加了骨矿物质密度（BMD），同时增加了肝脏和子宫的重量，而E₂×3D₆仅以剂量依赖方式增加了BMD。给药后4小时，E₂×3D₆增强了OVX小鼠骨基质蛋白（骨桥蛋白、骨唾液蛋白、I型胶原α）信使核糖核酸的表达，但E₂的作用非常轻微。这些结果表明，E₂前药被输送到骨骼，在那里它逐渐释放E₂，从而改善骨质流失。这种酸性寡肽似乎是选择性药物输送到骨骼的良好候选物。
