OSTEOTROPIC DRUG-DELIVERY SYSTEM (ODDS) BASED ON BISPHOSPHONIC PRODRUG .5. BIOLOGICAL DISPOSITION AND TARGETING CHARACTERISTICS OF OSTEOTROPIC ESTRADIOL

An osteotropic drug delivery system (ODDS) based on a bisphosphonic pr odrug has been developed for 17 beta-estradiol (E-2) to improve patien t compliance in estrogen replacement therapy of postmenopausal osteopo rosis. The biological disposition and the targeting efficiency of a bi sphosphonic prodrug of E-2, disodium [17 -(3'-hydroxy-1',3',5'-estratr iengloxy)carbonpropyl carboxamidomethylene]bisphosphonate (E-2-BP), wa s 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 13.5 d. The bone concentration of regenerat ed E-2 was maintained throughout 286. In contrast, E-2 injected intrav enously showed extremely low bone distribution and rapid clearance fro m the bone, and E-2 administered orally showed even lower bone distrib ution. Therapeutic availability (TA)and drug targeting index (DTI), wh ich were calculated on the basis of the AUCs for E-2 in the bone and p lasma after injection of E-2-BP and E-2, were 64.6 and 451, respective ly. These results suggest that ODDS has a potential to improve not onl y the apparent potency but also the therapeutic index of E-2. As compa red with the conventional estrogenic products, E-2-BP should improve p atient compliance with lower adverse effects and less frequent medicat ion in long-term estrogen replacement therapy.