OSTEOTROPIC DRUG-DELIVERY SYSTEM (ODDS) BASED ON BISPHOSPHONIC PRODRUG .3. PHARMACOKINETICS AND TARGETING CHARACTERISTICS OF OSTEOTROPIC CARBOXYFLUORESCEIN

An osteotropic drug delivery system (ODDS) based on a bisphosphonic pr odrug has been developed as a novel method for site-specific and contr olled delivery of drugs to the bone. The pharmacokinetics and the targ eting efficiency of a bisphosphonic prodrug of carboxyfluorescein (CF) , disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphon ate (CF-BP), was investigated in rats. After intravenous injection, CF -BP was rapidly taken up into the skeleton, and subsequently cleared f rom the bone by hydrolysis of its ester linkage at a half-life of 3.2 days. On the other hand, the bone concentration of regenerated CF grad ually increased to reach the maximum at 14 days and slowly decreased u p to 56 days. Kinetical analysis revealed that bone tissue acts as a r eservoir of regenerated CF to supply the parent compound into the syst emic circulation. In contrast with CF-BF, CF injected intravenously sh owed rapid clearance from the plasma and extremely low bone distributi on. Therapeutic availability (TA) and drug targeting index (DTI), whic h were calculated on the basis of the AUCs for CF in the bone and plas ma after injection of CF-BP and CE were 1551 and 6689, respectively. T hese results suggest that ODDS has a potential to improve not only app arent potency but also therapeutic index of the drugs which exhibit th eir pharmacological effects in the bone.