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Relationship Between Physicochemical and Osteotropic Properties of Bisphosphonic Derivatives: Rational Design for Osteotropic Drug Delivery System (ODDS)

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Abstract

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 ∼ −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.

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Authors and Affiliations

  1. Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Company, Osaka, Japan

    Hideki Hirabayashi

  2. Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Company, 1–6, 2–chome, Kashima, Yodogawa–ku, Osaka, 532–8514, Japan

    Hideki Hirabayashi, Taiji Sawamoto, Jiro Fujisaki, Yuji Tokunaga, Sumihisa Kimura & Takehisa Hata

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  1. Hideki Hirabayashi
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  2. Taiji Sawamoto
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  5. Sumihisa Kimura
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Hirabayashi, H., Sawamoto, T., Fujisaki, J. et al. Relationship Between Physicochemical and Osteotropic Properties of Bisphosphonic Derivatives: Rational Design for Osteotropic Drug Delivery System (ODDS). Pharm Res 18, 646–651 (2001). https://doi.org/10.1023/A:1011033326980

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