Hirabayashi Hideki, Sawamoto Taiji, Fujisaki Jiro, Tokunaga Yuji, Kimura Sumihisa, Hata Takehisa
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Company, Osaka, Japan.
Biopharm Drug Dispos. 2002 Nov;23(8):307-15. doi: 10.1002/bdd.323.
Rat pharmacokinetics and in vivo disposition of a novel bisphosphonic prodrug of diclofenac (DIC-BP), synthesized with the aim of osteotropic delivery of diclofenac, were determined at whole body, organ and cellular levels in a dose range 0.32-10mg/kg. With an increase in injected dose, total body clearance was decreased while the distribution volume at steady state (V(dss)) was reduced and plasma half-life was prolonged. Over 50% of a dose of DIC-BP was selectively transported into osseous tissues after intravenous injection into rats at doses up to 1mg/kg. As dose increased, the skeletal distribution decreased with hepatic and splenic accumulations increasing. The intrahepatic distribution at 10mg/kg revealed that liver macrophages play a significant role in hepatic uptake of DIC-BP. This is consistent with general arguments that bisphosphonates themselves cannot distribute in soft tissues, but are taken up by the reticuloendothelial system as foreign substances when they form large complexes or aggregate with endogenous metals in plasma. Therefore, to optimize the osteotropic delivery of diclofenac via a bisphosphonic prodrug, the dosage regimen should be such that plasma concentration of DIC-BP is maintained at a level lower than that required for precipitate formation of complexes, similar to the usage of other bisphosphonates.
为实现双氯芬酸的趋骨性递送而合成的新型双氯芬酸双膦酸前药（DIC-BP）在大鼠体内的药代动力学及体内处置情况，于0.32 - 10mg/kg剂量范围内在整体、器官和细胞水平进行了测定。随着注射剂量的增加，全身清除率降低，稳态分布容积（V(dss)）减小，血浆半衰期延长。静脉注射剂量高达1mg/kg的DIC-BP后，超过50%的剂量选择性转运至骨组织。随着剂量增加，骨骼分布减少，肝脏和脾脏蓄积增加。10mg/kg剂量时的肝内分布显示，肝巨噬细胞在DIC-BP的肝脏摄取中起重要作用。这与一般观点一致，即双膦酸盐本身不能分布于软组织中，但当它们在血浆中形成大的复合物或与内源性金属聚集时，会作为外来物质被网状内皮系统摄取。因此，为通过双膦酸前药优化双氯芬酸的趋骨性递送，给药方案应使DIC-BP的血浆浓度维持在低于复合物沉淀形成所需的水平，这与其他双膦酸盐的使用情况类似。
