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Quantitative and Comparative Analysis of Urinary Steroid Levels upon Treatment of an Anti-Diabetic Drug, CKD-501 using Gas Chromatography-Mass Spectrometry

  • Sadanala, Krishna Chaitanya (Integrated Omics Center, Korea Institute of Science and Technology) ;
  • Jung, Byung-Hwa (Integrated Omics Center, Korea Institute of Science and Technology) ;
  • Jang, In-Jin (Department of Pharmacology, Clinical Pharmacology & Clinical Trials Center, Seoul National University College of Medicine & Hospital) ;
  • Chung, Bong-Chul (Integrated Omics Center, Korea Institute of Science and Technology)
  • 투고 : 2011.01.26
  • 심사 : 2011.02.17
  • 발행 : 2011.02.20

초록

Urinary steroid levels were investigated in the treatment of CKD-501, a new anti-diabetic drug candidate. CKD-501 was administered orally at the dosage of 1, 2, 4 mg/day for 7 days to normal men (n=18). Urine was collected before, during and after stopping the drug administration and the urinary level of androgen, estrogen, progestin and corticoids were quantified using GC-MS (gas chromatography-mass spectrometry). Only urinary corticosteroid and an androgen, DHEA levels among all the analyzed steroids, have been found to increase progressively, reaching significant levels on the last day of drug treatment and later declined after the drug treatment is withdrawn. Therefore, it was thought that an increase in the urinary corticoid and DHEA levels could be a characteristic of CKD-501, since it prominently acts on the glucose sensitivity and suppresses the triglyceride levels. In conclusion, it was found that CKD-501, an anti-diabetic drug candidate, affects the glucocorticoid and DHEA levels and it plays a crucial role in glucose homeostasis.

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참고문헌

  1. Baxter, J.D., Rousseau, G.G., 1979. Glucocorticoid hormone action: an overview. Monogr. Endocrinol. 12, 1-24.
  2. Berthiaume, M., Sell, H., Lalonde, J., Gelinas, Y., Tchernof, A., Richard, D., Deshaies, Y., 2004. Actions of PPARγ agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids. Am J. Physiol. Regul. Integr. Comp Physiol. 287, R1116-R1123. https://doi.org/10.1152/ajpregu.00339.2004
  3. Betz, M.J., Shapiro, I., Fassnacht, M., Hahner, S., Reincke, M., Beuschlein, F., 2005. Peroxisome proliferator-activated $receptor-{\gamma}$ agonists suppress adrenocortical tumor cell proliferation and induce differentiation. J. Clin. Endocrinol. Metab. 90, 3886-3896. https://doi.org/10.1210/jc.2004-1267
  4. Blaschke, F., Takata, Y., Caglayan, E., Law, R.E., Hsueh, W.A., 2006. Nuclear receptors as potential target for the treatment and prevention of cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 26, 28-40. https://doi.org/10.1161/01.ATV.0000191663.12164.77
  5. Desvergne, B., Michalik, L., Wahli, W., 2004. Be Fit or Be Sick: Peroxisome proliferator-activated receptors are down the road. Mol. Endocrinol. 18, 1321-1332. https://doi.org/10.1210/me.2004-0088
  6. Dzhamilja, S., Nadezhda, P., Enn, S., Alexander, Z., Allen, K., 2006. Dehydroepiandrosterone inhibits complex I of the mitochondrial respiratory chain and is neurotoxic In vitro and In vivo at high concentrations. Toxicological Sciences. 93(2), 348-356. https://doi.org/10.1093/toxsci/kfl064
  7. Ferre, P., 2004. The biology of peroxisome proliferator-activated receptors. Diabetes. 53, S43-S50. https://doi.org/10.2337/diabetes.53.2007.S43
  8. Freeman, D.A., Romero, A., 2003. Effects of troglitazone on intracellular cholesterol distribution and cholesterol-dependent cell functions in MA-10 Leydig tumor cells. Biochem. Pharmacol. 66, 307-313. https://doi.org/10.1016/S0006-2952(03)00234-X
  9. Froment, P., Gizard, F., Defever, D., Staels, B., Dupont, J., Monget, P., 2006. PPARs and RXRs in male and female fertility and reproduction. J. Endocrinol. 189, 199-209. https://doi.org/10.1677/joe.1.06667
  10. Galina, A., Roberto, A.S.S., Zoltan, B., Radina, M.K., Alex, O., 2005. Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue. Am J. Physiol. Endocrinol. Metab. 288, E957-E964. https://doi.org/10.1152/ajpendo.00442.2004
  11. Harris, M.I., Flegal, K.M., Cowie, C.C., Eberhardt, M.S., Goldstein, D.E., Little, R.R., Wiedmeyer, H.M., Byrd-Holt, D.D., 1998. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. Diabetes Care. 21, 518-524. https://doi.org/10.2337/diacare.21.4.518
  12. Hevener, A.L., Olefsky, J.M., Reichart, D., Nguyen M.T.A., Bandyopadyhay, G., Leung, H.Y., Watt, M.J., Benner, C., Febbraio, M.A., Nguyen, A.K., Folian, B., Subramaniam, S., Gonzalez, F.J., Glass, C.K., Ricote, M., 2007. Macrophage $PPAR{\gamma}$ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J. Clin. Invest. 117, 1658-1669. https://doi.org/10.1172/JCI31561
  13. Jay, M.A., Ren, J., 2007. Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus. Curr. Diabetes. 3, 33-39. https://doi.org/10.2174/157339907779802067
  14. Kassirer, J.P., 1971. Clinical evaluation of kidney function − glomerular function. N. Engl. J. Med. 285, 385-389. https://doi.org/10.1056/NEJM197108122850706
  15. Kempna, P., Hofer, G., Mullis, P.E., Fluck, C.E., 2007. Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. Mol. Pharmacol. 71, 787-798.
  16. Lee, J. H., Woo, T.A., Hwang, I.C., Kim, C. Y., Kim, D. D., Shim, C. K., Chung, S.J., 2009. Quantification of CKD-501, lobeglitazone, in rat plasma using a liquid-chromatography/tandem mass spectrometry method and its applications to pharmacokinetic studies. J. Pharmaceut. Biomed. Anal. 50, 872-877. https://doi.org/10.1016/j.jpba.2009.06.003
  17. Moon, J.Y., Jung, H.J., Moon, M.H., Chung, B.C., Choi, M.H., 2009. Heat-map visualization of gas chromatography-mass spectrometry based quantitative signatures on steroid metabolism. J. Am. Soc. Mass Spectrom. 20, 1626-1637. https://doi.org/10.1016/j.jasms.2009.04.020
  18. Norgren, S., Arner, P., Luthman, H., 1994. Insulin receptor ribonucleic acid levels and alternative splicing in human liver, muscle, and adipose tissue: tissue specificity and relation to insulin action. J. Clin. Endocrinol. Metab. 78, 757-762. https://doi.org/10.1210/jc.78.3.757
  19. Orasanu, G., Ziouzenkova, O., Devchand, P.R., Nehra, V., Hamdy, O., Horton E.S., Plutzky, J., 2008. The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptoralpha-dependent manner in vitro and in vivo in mice. J. Am. Coll. Cardiol. 52, 869-881. https://doi.org/10.1016/j.jacc.2008.04.055
  20. Tomilson, J.W., Joanne, F., Christopher, G., Hughes, B.A., Susan, V. H., Paul, M. S., 2008. Impaired glucose tolerance and insulin resistance are associated with increased adipose $11{\beta}-hydroxysteroid$ dehydrogenase type 1 expression and elevated hepatic $5{\alpha}-reductase$ activity. Diabetes. 57, 2652-2660. https://doi.org/10.2337/db08-0495
  21. Wang, Q., Dryden, S., Frankish, H. M., Bing, C., Pickavance, L., Hopkins, D., Buckingham, R., Williams, G., 1997. Increased feeding in fatty Zucker rats by the thiazolidinedione BRL 49653 (rosiglitazone) and the possible involvement of leptin and hypothalamic neuropeptide Y. Br. J. Pharmacol. 122, 1405-1410. https://doi.org/10.1038/sj.bjp.0701535