Chemistry:Troglitazone

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Short description: Chemical compound
Troglitazone
Troglitazone.svg
Clinical data
Trade namesRezulin, Resulin, Romozin, Noscal
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration		By mouth (tablets)
ATC code
Legal status
Legal status
  • Production and promotion ceased
Pharmacokinetic data
Elimination half-life16–34 hours
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC24H27NO5S
Molar mass441.54 g·mol−1
3D model (JSmol)
Melting point184 to 186 °C (363 to 367 °F)
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Troglitazone is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for people with diabetes mellitus type 2.[1]

It was patented in 1983 and approved for medical use in 1997.[2] It was subsequently withdrawn.

Mechanism of action

Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone), works by activating peroxisome proliferator-activated receptors (PPARs).

Troglitazone is a ligand to both PPARα and – more strongly – PPARγ. Troglitazone also contains an α-Tocopherol moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown to reduce inflammation.[3] Troglitazone use was associated with a decrease of nuclear factor kappa-B (NF-κB) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellular transcription regulator for the immune response.

History

A 30-tablet pharmacy stock bottle of Rezulin (troglitazone) (400 mg) from Parke-Davis. Manufactured 1997. Shown also is one broken tablet. Tablet branding is PD353.

Troglitazone was developed by Daiichi Sankyo (Japan). In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. The Food and Drug Administration (FDA) medical officer assigned to evaluate troglitazone, John Gueriguian, did not recommend its approval due to potentially high liver toxicity; Parke-Davis complained to the FDA, and Gueriguian was subsequently removed from his post.[4] A panel of experts approved it in January 1997.[5] Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the United Kingdom market in December 1997, from the United States market in 2000, and from the Japan ese market soon afterwards. It did not get approval in the rest of Europe.

Troglitazone was developed as the first anti-diabetic drug having a mechanism of action involving the enhancement of insulin resistance. At the time, it was widely believed that such drugs, by addressing the primary metabolic defect associated with Type 2 diabetes, would have numerous benefits including avoiding the risk of hypoglycemia associated with insulin and earlier oral antidiabetic drugs. It was further believed that reducing insulin resistance would potentially reduce the very high rate of cardiovascular disease that is associated with diabetes.[6][7]

Parke-Davis/Warner Lambert submitted the diabetes drug Rezulin for FDA review on July 31, 1996. The medical officer assigned to the review, Dr. John L. Gueriguian, cited Rezulin's potential to harm the liver and the heart, and he questioned its viability in lowering blood sugar for patients with adult-onset diabetes, recommending against the drug's approval. After complaints from the drugmaker, Gueriguian was removed on November 4, 1996, and his review was purged by the FDA.[8][9] Gueriguian and the company had a single meeting at which Gueriguian used "intemperate" language; the company said its objections were based on inappropriate remarks made by Gueriguian.[10] Parke-Davis said at the advisory committee that the risk of liver toxicity was comparable to placebo and that additional data of other studies confirmed this.[11] According to Peter Gøtzsche, when the company provided these additional data one week after approval, they showed a substantially greater risk for liver toxicity.[12]

The FDA approved the drug on January 29, 1997, and it appeared in pharmacies in late March. At the time, Dr. Solomon Sobel, a director at the FDA overseeing diabetes drugs, said in a New York Times interview that adverse effects of troglitazone appeared to be rare and relatively mild.[13]

Glaxo Wellcome received approval from the British Medicines Control Agency (MCA) to market troglitazone, as Romozin, in July 1997.[14] After reports of sudden liver failure in patients receiving the drug, Parke-Davis and the FDA added warnings to the drug label requiring monthly monitoring of liver enzyme levels.[15] Glaxo Wellcome removed troglitazone from the market in Britain on December 1, 1997.[8] Glaxo Wellcome had licensed the drug from Sankyo Company of Japan and had sold it in Britain from October 1, 1997.[16][17]

On May 17, 1998, a 55-year-old patient named Audrey LaRue Jones died of acute liver failure after taking troglitazone. Importantly, she had been monitored closely by physicians at the National Institutes of Health (NIH) as a participant in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) diabetes prevention study.[18][19] This called into question the efficacy of the monitoring strategy. The NIH responded on June 4 by dropping troglitazone from the study.[9][20] Dr. David J. Graham, an FDA epidemiologist charged with evaluating the drug, warned on March 26, 1999 of the dangers of using it and concluded that patient monitoring was not effective in protecting against liver failure. He estimated that the drug could be linked to over 430 liver failures and that patients incurred 1,200 times greater risk of liver failure when taking Rezulin.[9][21] Dr. Janet B. McGill, an endocrinologist who had assisted in the Warner–Lambert's early clinical testing of Rezulin, wrote in a March 1, 2000 letter to Sen. Edward M. Kennedy (D-Mass.): "I believe that the company... deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies."[22]

On March 21, 2000, the FDA withdrew the drug from the market.[23] Dr. Robert I. Misbin, an FDA medical officer, wrote in a March 3, 2000 letter to Senator John Ashcroft of strong evidence that Rezulin could not be used safely. He was later threatened by the FDA with dismissal. [8][24] By that time, the drug had been linked to 63 liver-failure deaths and had generated sales of more than $2.1 billion for Warner-Lambert.[21] The drug cost $1,400 a year per patient in 1998.[17] Pfizer, which had acquired Warner-Lambert in February 2000, reported the withdrawal of Rezulin cost $136 million.[25]

Mechanisms of hepatotoxicity

Since the withdrawal in 2000, mechanisms of troglitazone hepatotoxicity have been extensively studied using a variety of in vivo,[26] in vitro,[27] and computational methods.[28] These studies have suggested that hepatotoxicity of troglitazone results from a combination of metabolic and nonmetabolic factors.[29] The nonmetabolic toxicity is a complex function of drug-protein interactions in the liver and biliary system. Initially, the metabolic toxicity was largely associated with reactive metabolite formation from the thiazolidinedione and chromane rings of troglitazone. Moreover, the formation of quinone and o-quinone methide reactive metabolites were proposed to be formed by metabolic oxidation of the hydroxy group (OH group) of the chromane ring.[26] Detailed quantum chemical analysis of the metabolic pathways for troglitazone has shown that quinone reactive metabolite is generated by oxidation of the OH group, but o-quinone methide reactive metabolite is formed by the oxidation of the methyl groups (CH3 groups) ortho to the OH group of the chromane ring.[28] This understanding has been recently used in the design of novel troglitazone derivatives with antiproliferative activity in breast cancer cell lines.[30]

Lawsuits

In 2009, Pfizer resolved all but three of 35,000 claims over its withdrawn diabetes drug Rezulin for a total of about $750 million. Pfizer, which acquired rival Wyeth for almost $64 billion, paid about $500 million to settle Rezulin cases consolidated in federal court in New York, according to court filings. The company also paid as much as $250 million to resolve state-court suits. In 2004, it set aside $955 million to end Rezulin cases.[31]

References

  1. ↑ "Adverse Diabetes Drug News Sends Warner-Lambert Down". The New York Times. 4 November 1997. https://www.nytimes.com/1997/11/04/business/adverse-diabetes-drug-news-sends-warner-lambert-down.html. 
  2. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 450. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA450. 
  3. ↑ "Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action?". The Journal of Clinical Endocrinology and Metabolism 86 (7): 3250–3256. July 2001. doi:10.1210/jcem.86.7.7564. PMID 11443197. 
  4. ↑ "Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights". wired.com. November 2008. https://www.wired.com/medtech/drugs/multimedia/2008/10/gallery_retired_drugs?slide=6&slideView=6. 
  5. ↑ "Risks of troglitazone apparent before approval in USA". Diabetologia 49 (6): 1454–1455. June 2006. doi:10.1007/s00125-006-0245-0. PMID 16601971. 
  6. ↑ "Effects of troglitazone on insulin sensitivity". Diabetic Medicine 13 (9 Suppl 6): S148–S150. September 1996. doi:10.1002/dme.1996.13.s6.148. PMID 8894499. 
  7. ↑ "Insulin resistance and the prevention of diabetes mellitus". The New England Journal of Medicine 331 (18): 1226–1227. November 1994. doi:10.1056/NEJM199411033311812. PMID 7935664. 
  8. ↑ 8.0 8.1 8.2 "NEW FDA: Rezulin Fast-Track Approval and a Slow Withdrawal". The Los Angeles Times. 20 December 2000. http://www.pulitzer.org/archives/6480. 
  9. ↑ 9.0 9.1 9.2 "The Rise and Fall of the Killer Drug Rezulin". The Los Angeles Times. 4 June 2000. http://articles.latimes.com/2000/jun/04/news/mn-37375. 
  10. ↑ "Report: FDA Removes Medical Officer". https://apnews.com/76dfa040579fe2d4f72b9b8f9df981d6. 
  11. ↑ Powerful medicines. New York: Vintage books. 2005. 
  12. ↑ Deadly medicines and organised crime : how big pharma has corrupted healthcare. London [u.a.]: Radcliffe Publ.. 2013. p. 185. ISBN 9781846198847. 
  13. ↑ "New Class of Diabetes Drug Is Approved". The New York Times. 31 January 1997. https://www.nytimes.com/1997/01/31/us/new-class-of-diabetes-drug-is-approved.html. 
  14. ↑ "Glaxo Wellcome gets approval for Romozin". ICIS News. 31 July 1997. http://www.icis.com/Articles/1997/07/31/34199/glaxo-wellcome-gets-approval-for-romozin.html. 
  15. ↑ "Approval package for Rezulin (troglitazone)". Center for Drug Evaluation and Research. U.S. Food and Drug Administration. 4 April 1997. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020720a_s001_thru_s007.pdf. 
  16. ↑ "Diabetes drug withdrawn from sale". BBC (British Broadcasting Corporation). 1 December 1997. http://news.bbc.co.uk/2/hi/uk_news/36090.stm. 
  17. ↑ 17.0 17.1 "Drug Makers at Threshold of a New Therapy; With a Dose of Biotechnology, Big Change Is Ahead in the Treatment of Diabetes". The New York Times. 17 January 1998. https://www.nytimes.com/1998/01/17/business/drug-makers-threshold-new-therapy-with-dose-biotechnology-big-change-ahead.html?pagewanted=all&src=pm. 
  18. ↑ The Diabetes Prevention Program Research Group (April 1999). "The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes". Diabetes Care 22 (4): 623–634. doi:10.2337/diacare.22.4.623. PMID 10189543. 
  19. ↑ "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". The New England Journal of Medicine 346 (6): 393–403. February 2002. doi:10.1056/NEJMoa012512. PMID 11832527. 
  20. ↑ "Troglitazone: the lesson that nobody learned?". Diabetologia 49 (1): 1–6. January 2006. doi:10.1007/s00125-005-0074-6. PMID 16362281. 
  21. ↑ 21.0 21.1 "FDA's Approval and Delay in Withdrawing Rezulin Probed". The Los Angeles Times. 16 August 2000. http://www.pulitzer.org/archives/6486. 
  22. ↑ "Fears Grow Over Delay in Removing Rezulin". The Los Angeles Times. 10 March 2000. http://www.pulitzer.org/archives/6483. 
  23. ↑ "2000 Safety Alerts for Human Medical Products". U.S. Food and Drug Administration. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm173081.htm. 
  24. ↑ "Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal". Los Angeles Times. March 17, 2000. http://articles.latimes.com/2000/mar/17/news/mn-9908. 
  25. ↑ "Pfizer Annual Report 2001". Pfizer. http://people.stern.nyu.edu/jbilders/Pdf/pfizer2001ar.pdf. 
  26. ↑ 26.0 26.1 "Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission". Chemical Research in Toxicology 14 (1): 62–70. January 2001. doi:10.1021/tx000180q. PMID 11170509. 
  27. ↑ "Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat". Molecular Pharmacology 59 (3): 627–635. March 2001. doi:10.1124/mol.59.3.627. PMID 11179459. 
  28. ↑ 28.0 28.1 "Toxic metabolite formation from Troglitazone (TGZ): new insights from a DFT study". Chemical Research in Toxicology 24 (7): 1113–1122. July 2011. doi:10.1021/tx200110h. PMID 21657230. 
  29. ↑ "Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review". Drug Metabolism and Pharmacokinetics 21 (5): 347–356. October 2006. doi:10.2133/dmpk.21.347. PMID 17072088. 
  30. ↑ "Synthesis of new troglitazone derivatives: anti-proliferative activity in breast cancer cell lines and preliminary toxicological study". European Journal of Medicinal Chemistry 51: 206–215. May 2012. doi:10.1016/j.ejmech.2012.02.044. PMID 22409968. 
  31. ↑ "Pfizer Ends Rezulin Cases With $205 Million to Spare". Bloomberg. March 31, 2009. https://www.bloomberg.com/apps/news?pid=newsarchive&sid=act0akCefQwo. 

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