Toxicological Research

  • 제20권3호
  • /
  • Pages.281-292
  • /
  • 2004
  • /
  • 1976-8257(pISSN)
  • /
  • 2234-2753(eISSN)
한국독성학회 (Korean Society of Toxicology & Korea Environmental Mutagen Society)
권호 표지

Single and Five-Week Oral Dose Toxicity Studies of Calcitriol and Alendronate Mixtures in Rats

  • Moon, Sung Won (Department of Pathophysiology, College of Pharmacy, Chung-Ang University) ;
  • Jin, Ji Yun (Department of Pathophysiology, College of Pharmacy, Chung-Ang University) ;
  • Lee, Jin Hee (Department of Pathophysiology, College of Pharmacy, Chung-Ang University) ;
  • Sim, Sang Soo (Department of Pathophysiology, College of Pharmacy, Chung-Ang University) ;
  • Kim, Chang Jong (Department of Pathophysiology, College of Pharmacy, Chung-Ang University)
  • 발행 : 2004.09.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

The purpose of this study was to assess the single and 5 week oral dose toxicity of calcitriol and alendronate combination (1 : 10,000) treatment for osteoporosis or Paget's disease in male and female rats. In single dose oral toxicity study, the values of $LD_{50}$ of calcitriol and alendronate mixture were 750.075 mg/kg in male rats and 775.0775 mg/kg in female rats, respectively. Body weight and food consumption were continuously increased after adminstration of calcitriol and alendronate mixtures, and there was no significant changes in body weight and food consumption in all groups. In five-week oral toxicity study of calcitriol and alendronate mixture at a dose of 0.2 $\mu\textrm{g}$ + 2 mg, 1 $\mu\textrm{g}$ + 10 mg, 5 $\mu\textrm{g}$ + 50 mg and 25 $\mu\textrm{g}$ + 250 mg, respectively, there was no mortality, abnormal behavior and appearance in all groups throughout the administration period (5 weeks) and recovery period (2 weeks). Dose-dependent changes in parameters of urinalysis and hematological analysis were not observed in male and female rats treated with calcitriol and alendronate mixtures. All the values of the parameters appeared to be in the normal range. These data indicate that both calcitriol and alendronate are drugs having low toxicity in rats. NOAEL of calcitriol and alendronate mixtures were 50.005 mg/kg in 5-week oral toxicity.

키워드

참고문헌

  1. Azuma, M., Sato, H., Oue, Y., Okabe, K., Ota, T., Tsuchimoto, M. and Kiyoki, M. (1995): Alendronate distributed on bone surfaces inhibits osteoclastic bone resorption in vitro and in experimental hypercalcemia models. Bone, 16, 215-245 https://doi.org/10.1016/8756-3282(94)00032-U
  2. Behrens, B. and Karber, G. (1935): Wie sind Rehenversuche fur biologische Ausvertungen am zweckmasigsten anzuordnen? Naunyn-Schmiedeberg's Archiv Experimentelle Pathologie und Pharmacologie, 177, 379-388
  3. Boonekamp, P.M., Van der Wee-Pals, L.J.A., Van Wijk-Van Lennep, M.M.L., Thesingh, C.W. and Bijvoet, O.L.M. (1986): Two modes of action of bisphosphonate on osteoclastic resorption of mineralized matrix. Bone Min., 1, 27-39
  4. Caniggia, A., Nuti, R. and Martini, G. et al. 1996: Efficacy and safety of long-term, open-label treatment with calcitriol in postmenopausal osteoporosis: a retrospective analysis. Curr. Ther. Res. Clin. Exp., 57, 857-869
  5. Canigga, A. and Vattimo, A. (1979): Effects of 1,25-dihydroxycholecalciferol on calcium absorption in post-menopausal osteoporosis. Clin. Endocrinol., 11, 99-103
  6. Carano, A., Teitelbaum, S.L., Konsek, J.D., Schlesinger, P.H. and Blair, H.C. (1990): Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J. Clin. Invest., 85, 456-461 https://doi.org/10.1172/JCI114459
  7. Fawcett, J. (1999): Physician's drug handbook 8th ed., Springhouse Corp., Springhouse, Pennsylvania, 149-150
  8. Frediani, B. Allegri, A., Bisgono, S. and Marcolongo, R. (1998): Effect of combined treatment of calcitriol plus alendronate on bone mass and bone turnover in postmenopausal osteoporosis two years of contineous treatment. Clinical Drug Invest., 5, 235-244
  9. Gallagher, J.C. (1990): Metabolic effects of synthetic calcitriol (Rocaltrol) in the treatment of postmenopausal osteoporosis. Metabolism, 39 Suppl.1, 27-29
  10. Inveresk Research International (1979): Standard Operating Procedures in Toxicology (Paget, G.E. and Thomson, R. eds.), MTP press, Lancaster, England
  11. James, E.F. and Reynolds, M. (1993): The Extra Pharmacopoeia (30th edition), The Pharmaceutical Press, London
  12. Korea Food and Drug Administration (1999): Guidelines for Toxicity Testing of Pharmaceuticals, Public Notice No.1999-61
  13. Kiriyama, T., Okamoto, S., Suzuki, H., Nagata, A., Izumi, M., Morii, H. and Nagatagi, S. (1989): Biological activity of 26, 26, 26, 27, 27, 27-hexa-fluoro-1, 25-dihydroxyvitamin D3 in the chick. Acta. Endoclinologica, 121, 520-524
  14. Lowik, C.W.G.M., Van der Pluijm, G., Van der Wee-pals, L.J.A., Bloys-Van Treslong-de Groot, H. and Bijvoet, O.L.M. (1988): Migration and phenotypic transformation of osteoclast precursors into mature osteoclasts. J. Bone Min. Res., 3, 185-192
  15. Malavolta, N., Zanardi, M., Veronesi, M., Ripamonti, C. and Gnudi, S. (1999): Calcitriol and alendronate combination treatment in menopausal women with low bone mass. Int. J. Tissue React., 21, 51-9
  16. Nagao, Y., Ishitobi, Y., Fukushima, S., awashima, H. and Kumagawa, M. (1990): Ym-175 inhibits osteoclast differentiation and bone resorbingaction of mature osteoclasts. J. Bone Min. Res., 5, S159
  17. Nakatsuka, K., Imanishi, Y., Morishima, Y., Sekiya, K., Sasao, K., Miki, T., Nishizawa, Y., Katsumata, T., Nagata, A., Murakawa, S. and Mori, H. (1992): Biological potency of a fluorinated vitamin D analogue in hypoparathyroidism. Bone and Mineral, 16, 73-81 https://doi.org/10.1016/0169-6009(92)90823-V
  18. Need, A.G., Horowitz, M., Philcox, J.C. and Nordin, B.E. (1985): 1,25-dihydroxycholecalciferol and calcium therapy in osteoporosis with calcium malabsorption. Miner. Electrolyte Metab., 11, 35-40
  19. Sahni, M., Guenther, H.L., Fleisch, H., Collin, P. and Martin, T.J. (1993): Bisphosphonates act on rat bone resorption through the mediation of osteoblasts. J. Clin. Invest., 91, 2004-2011 https://doi.org/10.1172/JCI116422
  20. Wendlova, J., Galbavy, S. and Paukovic, J. (1999): Paget's disease of bone--treatment with alendronate, calcium and calcitriol. Vnitr. Lek., 45, 602-605