Relationship between physicochemical and osteotropic properties of bisphosphonic derivatives: Rational design for Osteotropic Drug Delivery System (ODDS)

Purpose. The objective of this investigation is to develop a rational desig n of Osteotropic Drug Delivery System (ODDS), which we have proposed as a n ovel method for drug delivery to the skeleton via bisphosphonic prodrug, ba sed on the relationship between physicochemical and pharmacokinetic propert ies of bisphosphonates. Methods. The theoretical octanol/water partition coefficients (clog P) of 1 3 bisphosphonates were calculated by computer software, CLOGP ver. 3.05 (Da ylight C.I.S., Inc. Irvine, CA) and related to pharmacokinetic or osteotrop ic parameters after intravenous injection into rats. On the other hand, to optimize ODDS of diclofenac (DIC-BP), the effects of doses or infusion rate s on the in vivo disposition were investigated in relation to solubility pr oduct 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 similar to -0.914). The targeta bility of bisphosphonates to the skeleton was linearly decreased with an in crease in clog P value and the more hydrophilic bisphosphonates were suitab le for ODDS in bolus administration. On the other hand, DIC-BP, a relativel y lipophilic bisphosphonate, was effectively and selectively delivered to t he skeleton only when administered as a slow infusion to keep plasma concen tration lower than that calculated from Ksp value where DIC-BP could precip itate with calcium in the plasma circulation. Conclusions. Our results suggest the possibility of a rational design of OD DS via bisphosphonic prodrugs, after consideration of compound lipophilicit y and precipitability of bisphosphonate-calcium complex.