Nonclinical safety evaluation of muraglitazar, a novel PPARα/ γ agonist

Toxicological Sciences

Volumn 100, Issue 1, 2007, Pages 248-258

  Waites, Crystal R ^a   Dominick, Mark A ^a   Sanderson, Thomas P ^a   Schilling, Beth E ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

Agonist; Chronic toxicity; Dual PPAR ; Muraglitazar; Toxicology profile

Indexed keywords

MURAGLITAZAR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST;

ACUTE TOXICITY; ADIPOSE TISSUE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLOOD TOXICITY; CARCINOGENICITY; CARDIOTOXICITY; CHRONIC TOXICITY; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG EXPOSURE; DRUG SAFETY; DRUG SCREENING; EDEMA; EXPERIMENTAL MODEL; FEMALE; GENOTOXICITY; LIVER TOXICITY; MALE; MOUSE; NEUROTOXICITY; NONHUMAN; RAT; REPRODUCTIVE TOXICITY; SINGLE DRUG DOSE; TERATOGENICITY; TESTIS DISEASE; TOXICITY TESTING; TOXICOKINETICS;

ADMINISTRATION, ORAL; ANIMALS; CARCINOGENICITY TESTS; CONSUMER PRODUCT SAFETY; DOGS; FEMALE; GLYCINE; HYPOGLYCEMIC AGENTS; LETHAL DOSE 50; MACACA FASCICULARIS; MALE; MICE; MICE, INBRED ICR; OXAZOLES; PPAR ALPHA; PPAR GAMMA; PROMOTER REGIONS (GENETICS); RABBITS; RATS; RATS, SPRAGUE-DAWLEY; RISK ASSESSMENT; SPECIES SPECIFICITY; TOXICITY TESTS, CHRONIC; TRANS-ACTIVATION (GENETICS);

CANIS FAMILIARIS; MUS; ORYCTOLAGUS CUNICULUS; RATTUS;

EID: 35448951406     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfm193     Document Type: Article

References (50)

1. Actos® Summary basis of approval. (1999). (Generic name: Pioglitazone). Official FDA citation.
2. Arakawa, K., Ishihara, T., Aoto, M., Inamasu, M., Kitamura, K., and Saito, A. (2004). An antidiabetic thiazolidinedione induces eccentric cardiac hypertrophy by cardiac volume overload in rats. Clin. Exp. Pharmacol. Physiol 31, 8-13.
3. Avandia® Summary basis of approval. (1999). (Generic name: rosiglitazone). Official FDA citation.
4. Berger, J., and Moller, D. E. (2002). The mechanism of action of PPARs. Annu. Rev. Med 53, 409-435.
5. Boettcher, B., Fanelli, B., Stephen, Z., Caplan, S., and Sabio, M. (2003). Comparison of ligand binding affinities in the mouse and human PPARα and γ ligand binding domains. PPARs: Transcriptional Regulators of Metabolism and Metabolic Disease (B5); February 4-9, 2003; Keystone, Colorado: Keystone Symposium-PPARs (Abstract no 106).
6. Buse, J. B., Rubin, C. J., Frederich, R., Viraswami-Appanna, K., Lin, K. C., Montoro, R., Shockey, G., and Davidson, J. A. (2005). Muraglitazar, a dual (alpha/gamma) PPAR activator: A randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes. Clin. Ther. 27, 1181-1195.
7. Catalano, P. M., Nizielski, S. E., Shao, J., Preston, L., Qiao, L., and Friedman, J. E. (2002). Downregulated IRS-1 and PPARγ in obese women with gestational diabetes: Relationship to FFA during pregnancy. Am. J. Physiol. Endocrinol. Metab. 282, E522-E533.
8. Cox, S. L. (2005). Muraglitazar: An agent for the treatment of type 2 diabetes and associated dyslipidemia. Drugs Today 41, 579-587.
9. de la Iglesia, F. A., Herman, J. R., McGuire, E. J., Gough, A. W., and Masuda, H. (1998). Chronic toxicity study of the antidiabetic troglitazone in Wistar rats. Toxicologist 42(1-S), 50 (Abstract 246).
10. Devasthale, P., Chen, S., Jeon, Y., Qu, F., Shao, C., Wang, W., Zhang, H., Cap, M., Farrelly, D., Golla, R., et al. (2005). Design and synthesis of N-[(4-methoxyphenoxy) carbonyl]-N- 4-[2-(5-methyl-2-phenyl-4-oxazolyl) ethoxyl phenyl]methyl]glycine [muraglitazar/BMS-298585), a novel PPARα/γ] dual agonist with efficacious glucose and lipid-lowering activities. J. Med. Chem. 48, 2248-2250.
11. Dominick, M. A., White, M. R., Sanderson, T. P., Van Vleet, T. R., Cohen, S. E., Arnold, L. E., Tannehill-Gregg, S. H., Moehlenkamp, J. D., Waites, C. R., and Schilling, B. E. (2006). Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPAR α/γ agonist: Evidence for urolithiasis as the inciting event in the mode of action. Toxicol. Pathol. 34, 903-920.
12. El Hage, J. (2005). http://www.fda.gov/ohrms/dockets/ac/05/slides/ 2005-4169S2_02_02_FDA-ElHage.ppt. Accessed in July 2006.
13. Ghatnekar, G. S., Barnes, J. A., Dow, J. L., and Smoak, I. W. (2004). Hypoglycemia-induced changes in cell death and cell proliferation in the organogenesis-stage embryonic mouse heart. (Part A). Birth Defects Res 70, 121-131.
14. Gray, R. H., and de la Iglesia, F. A. (1984). Quantitative microscopy comparison of peroxisome proliferation by the lipid-regulating agent gemfibrozil in several species. Hepatology 4, 520-530.
15. Harrity, T., Farrelly, D., Tieman, A., Chu, C., Kunselman, L., Gu, L., Ponticiello, R., Cap, M., Qu, F., Shao, C., et al. (2006). Muraglitazar, a novel dual ({ alpha}/{gamma}) peroxisome proliferator-activated receptor activator, improves diabetes and other metabolic abnormalities and preserves [beta]-cell function in db/db mice. Diabetes 55, 240-248.
16. Herman, J. R., Metz, A. L., McGuire, E. J., and de la Iglesia, F. A. (1997). Subchronic toxicity of the antidiabetic troglitazone in Wistar rats. Toxicologist 36, 273 (Abstract 1387).
17. Hertz, R., Bishara-Shieban, J., and Bar-Tana, J. (1995). Mode of action of peroxisome proliferators as hypolipidemic drugs suppression of apolipoprotein C-III. J. Biol. Chem. 100(1), 248-259.
18. Horikoshi, H., Yoshioka, T., Nakamura, K., Matsunuma, N., Yamaguchi, K., and Sasahara, K. (1994). Troglitazone (CS-045), a new antidiabetic drug. Annu. Rep. Sankyo Res. Lab. 46, 1-57.
19. Horton, E. S., Whitehouse, F., Ghazzi, M. N., Venable, T. C., and Whitcomb, R. W. The Troglitazone Study Group (1998). Troglitazone in combination with sulfonylurea restores glycemio control in patients with type 2 diabetes. Diabetes Care 21, 1462-1469.
20. Ikeda, H., Taketomi, S., Sugiyama, Y., Shimura, Y., Sohda, T., Meguro, K., and Fujita, T. (1990). Effects of pioglitazone on glucose and lipid metabolism in normal and insulin resistant animals. Drug Res. 40(I), 156-162.
21. Kazumi, T., Hirano, T., Odaka, H., Ebara, T., Amano, N., Hozumi, T., Ishida, Y., and Yoshino, G. (1996). VLDL triglyceride kinetics in Wistar fatty rats, an animal model of NIDDM: Effects of dietary fructose alone or in combination with pioglitazone. Diabetes 45, 806-811.
22. Kersten, S., Desvergne, B., and Wahli, W. (2000). Roles of PPARs in health and disease. Nature 405, 421-424.
23. King, H., Auert, R. E., and Herman, W. H. (1998). Global burden of diabetes, 1995-2025. Diabetes Care 21, 1414-1431.
24. Klaunig, J. E., Babich, M. A., Baetche, K. P., Cook, J. C., Cotton, J. C., David, R. M., Deluca, J. G., Lai, D. Y., Mckee, R. H., Peters, J. M., et al. (2003). PPARα agonist-induced rodent tumors: Modes of action and human relevance. Crit. Rev. Toxicol. 33, 655-780.
25. Lee, M. K., Miles, P. D., Khoursheed, M., Gao, K. M., Moossa, A. R., and Olefsky, J. M. (1994). Metabolic effects of troglitazone on-fructose-induced insulin resistance in the rat. Diabetes 43 1435-1439.
26. Lehrke, M., and Lazar, M. A. (2005). The many faces of PPARγ. Cell 123, 993-999.
27. Martens, F. M. A. C., Visseren, F. L. J., Lemay, J., deKonig, E. J. P., and Rabelink, T. J. (2002). Metabolic and additional vascular effects of thiazolidinediones. Drugs 62(10), 1463-1480.
28. McGuire, E. J., Dethloff, L. A., Walsh, K. M., de la Iglesia, F. A., and Masuda, H. (1997) Subchronic toxicity of the antidiabetic troglitazone in B6C3F1 mice. Toxicologist 36, 273 (Abstract 1388).
29. Nahle, Z. (2004). PPAR trilogy from metabolism to cancer. Curr. Opin. Clin. Nutr. Metab. Care 7, 397-402.
30. Nesto, R. W., Bell, D., Bonow, R. O., Fonseca, V., Grundy, S. M., Horton, E. S., Winter, M. L., Porte, D., Semenkovich, C. F., Smith, S., et al. (2003). Thiazolidinedione use, fluid retention, and congestive heart failure. Circulation 108, 2941-2948.
31. PDR® Electronic Library™. (2004a). Avandia® (Generic name: rosiglitazone).
32. PDR® Electronic Library™. (2004b). Actos® (Generic name: pioglitazone).
33. Pickavance, L. C., Tadayyon, M., Widdowson, P. S., Buckingham, R. E., and Wilding, J. P. H. (1999). Therapeutic index for rosiglitazone in dietary obese rats: Separation of efficacy and haemodilution. Br. J. Pharmacol. 128, 1570-1576.
34. Rothwell, C. E., Bleavins, M. R., McGuire, E. J., de la Iglesia, F. A., and Masuda, H. (1997). 52-week oral toxicity study of troglitazone in cynomolgus monkeys. Toxicologist 36, 273 (Abstract 1386).
35. Rothwell, C. E., McGuire, E. J., Altrogge, D. M., Masuda, H., and de la Iglesia, F. A. (2002). Chronic toxicity in monkeys with thiazolidinedione antidiabetic agent troglitazone. J. Toxicol. Sci. 27(1), 35-47.
36. Saltiel, A. R., and Horikoshi, H. (1995). Thiazolidinediones are novel insulin-sensitizing agents. Curr. Opin. Endocrinol. Diabetes 2 341-347.
37. Saltiel, A. R., and Olefsky, J. M. (1996). Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45, 1661-1669.
38. Schoonjans, K., Staels, B., and Auwerx, J. (1996). Role of the peroxisome proliferator activated receptor (PPAR) in mediating effects of fibrates and fatty acids on gene expression. J. Lipid Res. 37, 907-925.
39. Smith, S. A. (2002). Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism. Biochem. Soc. Trans. 30(6), 1086-1090.
40. Sohda, T., Mizuno, K., Momose, Y., Ikeda, H., Fujita, T., and Meguro, K. (1992). Studies on antidiabetic agents. 11. Novel thiazolidinedione derivatives as potent hypoglycemic and hypolipidemic agents. J. Med. Chem. 35, 2617-2626.
41. Soria, A., Bocos, C., and Herrera, E. (2002). Opposite metabolic response to fenofibrate treatment in pregnant and virgin rats. J. Lipid Res. 43, 74-81.
42. Speigelman, B. M. (1998). PPAR-γ Adipogenic regulator and thiazolidinedione receptor. Diabetes 47, 507-514.
43. Staels, B., van Tol, A., Andreu, T., and Auwerx, J. (1992). Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat. Arterioscler. Thromb. 12 286-294.
44. Sugden, M. C., Greenwood, G. K., Smith, N. D., and Holness, M. J. (2003). Peroxisome proliferator-activated receptor-α activation during pregnancy attenuates glucose-stimulated insulin hypersecretion in vivo by increasing insulin sensitivity, without impairing pregnancy-induced increases in β-cell glucose sensing and responsiveness. Endocrinology 144(1), 146-153.
45. Tai, T., Jennermann, C., Brown, K. K., Oliver, B. B., MacGinnitie, M. A., Wilkison, W. O., Brown, H. R., Lehmanni, J. M., Kliewer, S. A., Morris, D. C., et al. (1996). Activation of the nuclear receptor peroxisome proliferator-activated receptor-γ promotes brown adipocyte differentiation. J. Biol. Chem. 271(47), 29909-29914.
46. Tannehill-Gregg, S. H., Sanderson T. P., Minnema, D., Voelker, R., Ulland, B., Cohen, S. M., Arnold, L. L., Schilling, B. E., Waites, C. R., and Dominick, M. A. (2007). Rodent carcinogenicity studies with the antidiabetic dual PPAR α and γ agonist muraglitazar. Toxicological Sciences, 98(1), 258-270.
47. Watkins, S. M., Reifsnyder, P. R., Pan, H., German, J. B., and Leiter, E. H. (2002). Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone. J. Lipid Res. 43, 1809-1817.
48. Wells, G. A. H., and Wells, M. (1989). Neuropil vacuolation in brain: A reproducible histological processing artefact. J. Comp. Pathol. 101, 355-362.
49. Williams, G. D., Deldar, A., Jordan, W. H., Gries, C., Long, G. G., and Dimarchi, R. D. (1993). Subchronic toxicity of the thiazolidinedione, Tanabe-174 (LY282449) in the rat and dog. Diabetes 42 Suppl.), 186.
50. Yki-Jarvinen, H. (2004). Thiazolidinediones. N. Engl. J. Med. 351, 1106-1118.