Summary
Clodronate (dichloromethylene bisphosphonate) accumulates extensively in bone by binding to hydroxyapatite crystals. In an hypo-osmotic vehicle, it accumulates also in the spleen and, to a lesser extent, in the liver of mice and rats. In the present study, the effects of parenteral routes of administration (intravenous, intraperitoneal, and subcutaneous), drug dose, and injection vehicle on the distribution of [14C]-clodronate were studied in mice. The route of drug injection had no effect on the deposition of clodronate in bone. Either deionized water or iso-osmotic saline used as vehicles for intravenous administration of the drug caused equal and dose-dependent accumulation in bone. In iso-osmotic glucose, however, the osseous deposition of the drug was 2.2–2.5 times lower than in the other vehicles (water, saline, choline chloride). Clodronate accumulated in spleen and liver only after intravenous injection when the drug was in hypo-osmotic vehicle, and the process was saturable at high doses. The hypotonic vehicle probably causes a local hemolysis, and clodronate forms complexes with erythrocyte iron, which is a prerequisite for ingestion of the drug by splenic and hepatic macrophages.
Similar content being viewed by others
References
Fleisch H. (1983): Bisphosphonates. Mechanism of action and clinical applications. In: Peck W.A. (ed.) Bone and Mineral Research, Annual 1. Amsterdam, Excerpta Medica, pp. 319–357.
Conrad K.A., Lee S.M. (1981): Clodronate kinetics and dynamics. Clin. Pharmacol. Ther., 30, 114–120.
Pentikäinen P.J., Elomaa I., Nurmi A.-K., Kärkkäinen S. (1989): Pharmacokinetics of clodronate in patients with metastatic breast cancer. Int. J. Clin. Pharmacol. Ther. Toxicol., 27, 222–228.
Mönkkönen J., Ylitalo P., Elo H.A., Airaksinen M.M. (1987): Distribution of14C-clodronate (dichloromethylene bisphosphonate) disodium in mice. Toxicol. Appl. Pharmacol., 89, 287–292.
Mönkkönen J. (1988): A one year follow-up study of the distribution of14C-clodronate in mice and rats. Pharmacol. Toxicol., 62, 51–53.
Mönkkönen J., Urtti A., Paronen P., Elo H.A., Ylitalo P. (1989): The uptake of clodronate (dichloromethylene bisphosphonate) by macrophages in vivo and in vitro. Drug Metab. Dispos., 17, 690–693.
Harington J.S., Miller K., Macrab G. (1971): Hemolysis by asbestos. Envir. Res., 4, 95–117.
Collan Y., Kosma V.-M., Anttonen H., Kulju T. (1986): Toxicity of richterite in hemolysis test and macrophage cultures. Arch. Toxicol., Suppl. 9, 292–295.
Michael W.R., King W.R., Wakim J.M. (1972): Metabolism of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) in the rat, rabbit, dog, and monkey. Toxicol. Appl. Pharmacol., 21, 503–515.
Van Duzee B.F., Sumberg R.J., Benedict J.J. (1980): Effect of etidronate disodium on filterability of sickle erythrocytes. J. Pharm. Sci., 69, 599–600.
Goy W., Crowe W.J. (1976): Splenic accumulation of99mTc-diphosphonate in a patient with sickle cell disease: Case report. J. Nucl. Med., 17, 108–109.
Winter P.F. (1976): Splenic accumulation of99mTc-diphosphonate. J. Nucl. Med., 17, 850.
Van Rooijen N., Van Nieuwmegen R. (1984): Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. An enzyme-histochemical study. Cell Tissue Res., 238, 355–358.
Mökkönen J., Koponen H.-M., Ylitalo P. (1990): Comparision of the distribution of three bisphosphonates in mice. Pharmacol. Toxicol., 66, 297–298.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mönkkönen, J., Ylitalo, P. The tissue distribution of clodronate (dichloromethylene bisphosphonate) in mice. The effects of vehicle and the route of administration. Eur. J. Drug Metab. Pharmacokinet. 15, 239–243 (1990). https://doi.org/10.1007/BF03190210
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03190210