Fujisaki J, Tokunaga Y, Sawamoto T, Takahashi T, Kimura S, Shimojo F, Hata T
Pharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Company Ltd., Osaka, Japan.
J Drug Target. 1996;4(2):117-23. doi: 10.3109/10611869609046270.
An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. The pharmacokinetics and the targeting efficiency of a bisphosphonic prodrug of carboxyfluorescein (CF), disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP), was investigated in rats. After intravenous injection, CF-BP was rapidly taken up into the skeleton, and subsequently cleared from 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 gradually increased to reach the maximum at 14 days and slowly decreased up to 56 days. Kinetical analysis revealed that bone tissue acts as a reservoir of regenerated CF to supply the parent compound into the systemic circulation. In contrast with CF-BP, CF injected intravenously showed rapid clearance from the plasma and extremely low bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for CF in the bone and plasma after injection of CF-BP and CF, were 1551 and 6689, respectively. These results suggest that ODDS has a potential to improve not only apparent potency but also therapeutic index of the drugs which exhibit their pharmacological effects in the bone.
一种基于双膦酸前药的骨靶向给药系统（ODDS）已被开发出来，作为一种将药物特异性地、可控地递送至骨骼的新方法。研究了羧基荧光素（CF）双膦酸前药二钠（荧光素 - 6 - 羰氧基）乙酰氨基亚甲基双膦酸盐（CF - BP）在大鼠体内的药代动力学和靶向效率。静脉注射后，CF - BP迅速被骨骼摄取，随后通过其酯键水解从骨骼中清除，半衰期为3.2天。另一方面，再生CF的骨浓度逐渐升高，在14天时达到最大值，并在56天内缓慢下降。动力学分析表明，骨组织作为再生CF的储存库，将母体化合物供应到体循环中。与CF - BP相比，静脉注射的CF从血浆中迅速清除，骨分布极低。根据注射CF - BP和CF后骨骼和血浆中CF的AUC计算得出的治疗可用性（TA）和药物靶向指数（DTI）分别为1551和6689。这些结果表明，ODDS不仅有可能提高在骨骼中发挥药理作用的药物的表观效力，还能提高其治疗指数。
