Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
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Absorption, Distribution, Metabolism, and Excretion of CKD-732, a Novel Antiangiogenic Fumagillin Derivative, in Rats, Mice, and Dogs

  • Published : 2004.02.01
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Abstract

The pharmacokinetics of CKD-732 (6-0-4-[dimethyl-aminoethoxy)cinnamoyl]-fumagillolㆍhemioxalate) was investigated in male SD rats and beagle dogs after bolus intravenous administration. The parent compound and metabolites obtained from in vitro and in vivo samples were determined by LC/MS. The main metabolite was isolated and identified as an N-oxide form of CKD-732 by NMR and LC/MS/MS. CKD-732 was metabolized into either M11 or others by rapid hydroxylation, demethylation, and hydrolysis. The blood level following the intravenous route declined in first-order kinetics with $T_{1}$2/$\beta$ values of 0.72-0.78 h for CKD-732 and 0.92-1.09 h for M11 in rats at a dose of 7.5-30 mg/kg. In dogs, $T_{1}$2/$\beta$ values of CKD-732 and M11 were 1.54 and 1.79 h, respectively. Moreover, AUC values increased dose dependently for CKD-732 and M11 in rats and dogs. The CLtot and Vdss did not change significantly with increasing dose, indicating linear pharmacokinetic patterns. The excretion patterns through the urine, bile, and feces were also examined in the animals. The total amount excreted in urine, bile, and feces was 2.13% for CKD-732 and 1.29% for M11 in rats, and 1.58% for CKD-732 and 2.28% for M11 in dogs.

Keywords

References

  1. Brem, H. and Folkman, J., Analysis of experimental anti-angiogenic therapy. J. Pediatr. Surg., 28, 445-450; Discussion 450-451 (1993) https://doi.org/10.1016/0022-3468(93)90246-H
  2. Cretton-Scott, E., Placidi, L., McClure, H., Anderson, C. D., and Sommadossi, J. P., Pharmacokinetics and metabolism of O-( chloroacetyl-carbamoyl) fumagillol (TNP-470, AGM-1470) in rhesus monkeys. Cancer Chemother. Pharmacol., 38, 117-122 (1996) https://doi.org/10.1007/s002800050458
  3. Dipaolo, J., Tarbell, D., and Moore G., Studies on the carcinolytic activity of fumagillin and some of its derivatives. Antibiot. Annu., 541-546 (1958-1959)
  4. Folkman, J. and Klagsbrun, M., Angiogenic factors. Science, 235,442-447 (1987) https://doi.org/10.1126/science.2432664
  5. Folkman, J., Tumor angiogenesis. Adv. Cancer Res., 43, 175-203 (1985)
  6. Folkman, J., Anti-angiogenesis: new concept for therapy of solid tumors. Ann. Surg., 175,409-416 (1972) https://doi.org/10.1097/00000658-197203000-00014
  7. Folkman, J., What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer lnst., 82, 4-6 (1990) https://doi.org/10.1093/jnci/82.1.4
  8. Ingber, D., Fujita, T., Kishimoto, S., Sudo, K., Kanamaru, T., Brem, H., and Folkman, Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature, 348, 555-557 (1990) https://doi.org/10.1038/348555a0
  9. Killough, J., Magill, G., and Smith, R., The treatment of amoebiasis with fumagillin. Science,115, 71-72 (1952) https://doi.org/10.1126/science.115.2977.71
  10. Kusaka, M., Sudo, K., Fujita, T., Marui, S., Itoh, F., Ingber, D., and Folkman, J., Potent anti-angiogenic action of AGM-1470: comparison to the fumagillin parent. Biochem. Biophys. Res. Cammun., 174, 1070-1076(1991) https://doi.org/10.1016/0006-291X(91)91529-L
  11. Lee, H. S., Kim, H. Y., Sohn, Y. S., Choi, W. K., Son, H. J., Lee, S. S., Myung, S.-W., Kim, J. K., Ahn, S. K., and Hong, C. I., Metabolism and Pharmacokinetic study of CKD-732. American Association for Cancer Research (93rd AACR), 43, 181 (2002)
  12. Myung, S. W., Kim, H. Y., Min, H. K., Kim, D. H., Kim, M. S., Cho, H., W., Lee, H. S., Kim, J. K., and Hong, C. I., The identification of in vitro metabolites of CKD-732 by liquid chromatography/tandem mass spectrometry. Rapid Cammun. Mass Spectrom., 16,2048-2053 (2002) https://doi.org/10.1002/rcm.830
  13. Park, H. J., Shon, Y. S., Son, H. J., Moon, S. K., Kim, J. G., Kim, J. K., Ahn, S. K., and Hong, C. I., Combination chemotherapy and preliminary toxicity of CKD-732, a novel fumagillin derivative. American Association for Cancer Research (92nd AACR), 42, 87 (2001)
  14. Placidi, L., Cretton-Scott, E., De Sousa, G., Rahmani, R., Placidi, M., and Sommadossi, J. P., Disposition and metabolism of the angiogenic moderator O-(chloroacetylcarbamoyl) fumagillol (TNP-470, AGM-1470) in human hepatocytes and tissue micorosomes. Cancer Res., 55, 3036-3042 (1995).
  15. Placidi, L., Cretton-Scott, E., De Sousa, G., Rahmani, R., Placidi, M. and Sommadossi, J. P., Interspecies variability of TNP-470 metabolism, using primary monkey, rat and dog cultured hepatocytes. Drug Metab. Dispos., 25, 94-99 (1997)
  16. Placidi, L., Cretton-Scott, E., Eckoff, D., Bynon, S., and Sommadossi, J. P., Metabolic drug interactions between angiogenic inhibitor, TNP-470 and anticancer agents in primary cultured hepatocytes and microsomes, Drug Metab. Dispas., 27, 623-626 (1999)