Osteotropic Drug Delivery System (ODDS) Based on Bisphosphonic Prodrug. V. Biological Disposition and Targeting Characteristics of Osteotropic Estradiol

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An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed for 17β-estradiol (E_2) to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The biological disposition and the targeting efficiency of a bisphosphonic prodrug of E_2,disodium [17β-(3'-hydroxy-1', 3', 5'-estratrienyloxy)carbonylpropyl carboxamidomethylene]bisphosphonate (E_2-BP), was investigated in ovariectomized rats. After intravenous injection, E_2-BP was rapidly taken up into the bone and subsequently cleared from the bone at a half-life of 13.5d. The bone concentration of regenerated E_2 was maintained throughout 28d. In contrast, E_2 injected intravenously showed extremely low bone distribution and rapid clearance from the bone, and E_2 administered orally showed even lower bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for E_2 in the bone and plasma after injection of E_2-BP and E_2,were 64.6 and 451,respectively. These results suggest that ODDS has a potential to improve not only the apparent potency but also the therapeutic index of E_2. As compared with the conventional estrogenic products, E_2-BP should improve patient compliance with lower adverse effects and less frequent medication in long-term estrogen replacement therapy.
公益社団法人日本薬学会の論文
1997-11-15