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.
抄録全体を表示