首页> 外文期刊>Pharmaceutical research >Relationship between physicochemical and osteotropic properties of bisphosphonic derivatives: rational design for osteotropic drug delivery system (ODDS).
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Relationship between physicochemical and osteotropic properties of bisphosphonic derivatives: rational design for osteotropic drug delivery system (ODDS).

机译:双膦酸酯衍生物的理化性质与亲骨性之间的关系:亲骨性药物递送系统(ODDS)的合理设计。

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PURPOSE: The objective of this investigation is to develop a rational design of Osteotropic Drug Delivery System (ODDS), which we have proposed as a novel method for drug delivery to the skeleton via bisphosphonic prodrug, based on the relationship between physicochemical and pharmacokinetic properties of bisphosphonates. METHODS: The theoretical octanol/water partition coefficients (clog P) of 13 bisphosphonates were calculated by computer software, CLOGP ver. 3.05 (Daylight C.I.S., Inc. Irvine, CA) and related to pharmacokinetic or osteotropic parameters after intravenous injection into rats. On the other hand, to optimize ODDS of diclofenac (DIC-BP), the effects of doses or infusion rates on the in vivo disposition were investigated in relation to solubility product value (Ksp) of DIC-BP-calcium complex. RESULTS: Clog P had good correlations with total plasma clearance, apparent distribution volume and the fraction dose delivered to the whole skeleton after bolus injection into rats (r = -0.868 approximately -0.914). The targetability of bisphosphonates to the skeleton was linearly decreased with an increase in clog P value and the more hydrophilic bisphosphonates were suitable for ODDS in bolus administration. On the other hand, DIC-BP, a relatively lipophilic bisphosphonate, was effectively and selectively delivered to the skeleton only when administered as a slow infusion to keep plasma concentration lower than that calculated from Ksp value where DIC-BP could precipitate with calcium in the plasma circulation. CONCLUSIONS: Our results suggest the possibility of a rational design of ODDS via bisphosphonic prodrugs, after consideration of compound lipophilicity and precipitability of bisphosphonate-calcium complex.
机译:目的:本研究的目的是开发一种合理设计的正交各向异性药物输送系统(ODDS),我们将其设计为一种基于双膦酸前体药物向骨骼输送药物的新方法,它基于药物的理化性质和药代动力学性质之间的关系。双膦酸盐。方法:使用计算机软件CLOGP ver。计算出13种双膦酸酯的理论辛醇/水分配系数(clog P)。 3.05(Daylight C.I.S.,Inc. Inc.,Irvine,CA),与静脉内注入大鼠后的药代动力学或骨质疏松参数有关。另一方面,为了优化双氯芬酸的ODDS(DIC-BP),研究了剂量或输注速率对体内DIC-BP-钙复合物的溶解度产物值(Ksp)的影响。结果:推注大鼠后,Clog P与血浆总清除率,表观分布量和递送至整个骨骼的分数剂量具有良好的相关性(r = -0.868约-0.914)。双膦酸酯对骨架的靶向性随clog P值的增加而线性降低,亲水性更高的双膦酸酯适用于大剂量给药的ODDS。另一方面,只有当缓慢输注时,DIC-BP(一种相对亲脂性的双膦酸酯)才能有效地,选择性地传递到骨骼上,以保持血浆浓度低于由Ksp值计算得出的浓度,其中DIC-BP可能会与钙离子一起沉淀。血浆循环。结论:我们的结果表明,在考虑了化合物的亲脂性和双膦酸钙复合物的沉淀性之后,可以通过双膦酸前药合理设计ODDS。

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