View source for Troglitazone

{{short description|Chemical compound}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 470617744
| IUPAC_name = (''RS'')-5-(4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl)thiazolidine-2,4-dione
| image = Troglitazone.svg
| image_class = skin-invert-image
| width = 240px

<!-- Clinical data -->
| tradename =  Rezulin, Resulin, Romozin, Noscal
| pregnancy_US = B
| legal_status = Production and promotion ceased
| routes_of_administration = By mouth ([[Tablet (pharmacy)|tablets]])

<!-- Pharmacokinetic data -->
| bioavailability =  
| protein_bound =  
| metabolism =  
| elimination_half-life = 16–34 hours

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 97322-87-7
| ATC_prefix = A10
| ATC_suffix = BG01
| ATC_supplemental =  
| PubChem = 5591
| IUPHAR_ligand = 2693
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00197
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5389
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = I66ZZ0ZN0E
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00395
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9753
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 408

<!-- Chemical data -->
| C=24 | H=27 | N=1 | O=5 | S=1
| smiles = O=C1NC(=O)SC1Cc4ccc(OCC3(Oc2c(c(c(O)c(c2CC3)C)C)C)C)cc4
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GXPHKUHSUJUWKP-UHFFFAOYSA-N
| melting_point = 184
| melting_high = 186
}}
<!-- Definition and medical uses -->
'''Troglitazone''' is an [[antidiabetic]] and [[anti-inflammatory]] drug, and a member of the [[medication|drug]] class of the [[thiazolidinedione]]s. It was prescribed for people with [[diabetes mellitus type 2]].<ref name=NYT>{{cite news| vauthors = Fisher L |title=Adverse Diabetes Drug News Sends Warner-Lambert Down|url=https://www.nytimes.com/1997/11/04/business/adverse-diabetes-drug-news-sends-warner-lambert-down.html|access-date=12 December 2012|newspaper=The New York Times|date=4 November 1997}}</ref>  

<!-- Society and culture -->
It was patented in 1983 and approved for medical use in 1997.<ref>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=450 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA450 |language=en}}</ref> It was subsequently withdrawn.

==Mechanism of action==
Troglitazone, like the other [[thiazolidinedione]]s ([[pioglitazone]] and [[rosiglitazone]]), works by activating [[peroxisome proliferator-activated receptor]]s (PPARs).

Troglitazone is a [[Ligand (biochemistry)|ligand]] to both PPARα and – more strongly – PPARγ. Troglitazone also contains an [[α-Tocopherol]] [[Moiety (chemistry)|moiety]], potentially giving it [[vitamin E]]-like activity in addition to its PPAR activation. It has been shown to reduce [[inflammation]].<ref>{{cite journal | vauthors = Aljada A, Garg R, Ghanim H, Mohanty P, Hamouda W, Assian E, Dandona P | title = Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 7 | pages = 3250–3256 | date = July 2001 | pmid = 11443197 | doi = 10.1210/jcem.86.7.7564 | doi-access = free }}</ref> Troglitazone use was associated with a decrease of [[NF-κB|nuclear factor kappa-B]] (NF-κB) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellular [[Transcriptional regulation|transcription regulator]] for the immune response.

==History==
[[File:Rezulin.JPG|thumb|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 drug reaction|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.<ref>{{cite web | vauthors = Hintertheur A | date = November 2008 | url = https://www.wired.com/medtech/drugs/multimedia/2008/10/gallery_retired_drugs?slide=6&slideView=6 | title = Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights | work = wired.com }}</ref> A panel of experts approved it in January 1997.<ref>{{cite journal | vauthors = Cohen JS | title = Risks of troglitazone apparent before approval in USA | journal = Diabetologia | volume = 49 | issue = 6 | pages = 1454–1455 | date = June 2006 | pmid = 16601971 | doi = 10.1007/s00125-006-0245-0 | doi-access = free }}</ref>  Once the prevalence of adverse [[liver]] effects became known, troglitazone was withdrawn from the [[United Kingdom|British]] 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.<ref>{{cite journal | vauthors = Henry RR | title = Effects of troglitazone on insulin sensitivity | journal = Diabetic Medicine | volume = 13 | issue = 9 Suppl 6 | pages = S148–S150 | date = September 1996 | pmid = 8894499 | doi = 10.1002/dme.1996.13.s6.148 | s2cid = 34080394 }}</ref><ref>{{cite journal | vauthors = Keen H | title = Insulin resistance and the prevention of diabetes mellitus | journal = The New England Journal of Medicine | volume = 331 | issue = 18 | pages = 1226–1227 | date = November 1994 | pmid = 7935664 | doi = 10.1056/NEJM199411033311812 }}</ref>

[[Warner–Lambert|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.<ref name=LATimes /><ref name=Willman>{{cite news| vauthors = Willman D |title=The Rise and Fall of the Killer Drug Rezulin|url=https://www.latimes.com/archives/la-xpm-2000-jun-04-mn-37375-story.html|access-date=12 December 2012|newspaper=The Los Angeles Times|date=4 June 2000}}</ref> 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.<ref>{{cite web |url=https://apnews.com/76dfa040579fe2d4f72b9b8f9df981d6 |title=Report: FDA Removes Medical Officer |website=[[Associated Press]] }}</ref> 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.<ref name=Avorn>{{cite book| vauthors = Avorn J |title=Powerful medicines|year=2005|publisher=Vintage books|location=New York}}</ref> According to [[Peter Gøtzsche]], when the company provided these additional data one week after approval, they showed a substantially greater risk for liver toxicity.<ref name=gotzsche>{{cite book| vauthors = Gøtzsche P |title=Deadly medicines and organised crime : how big pharma has corrupted healthcare|year=2013|publisher=Radcliffe Publ.|location=London [u.a.]|isbn=9781846198847|page=185}}</ref>

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.<ref name=NYTapprove>{{cite news| vauthors = Leary W |title=New Class of Diabetes Drug Is Approved|url=https://www.nytimes.com/1997/01/31/us/new-class-of-diabetes-drug-is-approved.html|access-date=12 December 2012|newspaper=The New York Times|date=31 January 1997}}</ref>

[[Glaxo Wellcome]] received approval from the [[Medicines and Healthcare products Regulatory Agency|British Medicines Control Agency]] (MCA) to market troglitazone, as Romozin, in July 1997.<ref name=ICIS>{{cite news| vauthors = Sinclair N |title=Glaxo Wellcome gets approval for Romozin |url= http://www.icis.com/Articles/1997/07/31/34199/glaxo-wellcome-gets-approval-for-romozin.html|access-date=12 December 2012|newspaper=ICIS News|date=31 July 1997}}</ref> 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.<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020720a_s001_thru_s007.pdf | archive-url = https://web.archive.org/web/20141105125707/http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020720a_s001_thru_s007.pdf | archive-date = 5 November 2014 |title= Approval package for Rezulin (troglitazone) | date = 4 April 1997 | work = Center for Drug Evaluation and Research | publisher = U.S. Food and Drug Administration }}</ref> Glaxo Wellcome removed troglitazone from the market in Britain on December 1, 1997.<ref name=LATimes>{{cite news| vauthors = Willman D |title=NEW FDA: Rezulin Fast-Track Approval and a Slow Withdrawal|url=http://www.pulitzer.org/archives/6480|access-date=12 December 2012|newspaper=The Los Angeles Times|date=20 December 2000}}</ref> Glaxo Wellcome had licensed the drug from [[Daiichi Sankyo|Sankyo Company]] of Japan and had sold it in Britain from October 1, 1997.<ref name=BBC>{{cite news| publisher = British Broadcasting Corporation|title=Diabetes drug withdrawn from sale|url=http://news.bbc.co.uk/2/hi/uk_news/36090.stm|access-date=12 December 2012|newspaper=BBC|date=1 December 1997}}</ref><ref name=Fisher>{{cite news| vauthors = Fisher L |title=Drug Makers at Threshold of a New Therapy; With a Dose of Biotechnology, Big Change Is Ahead in the Treatment of Diabetes|url=https://www.nytimes.com/1998/01/17/business/drug-makers-threshold-new-therapy-with-dose-biotechnology-big-change-ahead.html?pagewanted=all&src=pm|access-date=12 December 2012|newspaper=The New York Times|date=17 January 1998}}</ref>

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.<ref name=NIH>{{cite journal | title = The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes | journal = Diabetes Care | volume = 22 | issue = 4 | pages = 623–634 | date = April 1999 | pmid = 10189543 | pmc = 1351026 | doi = 10.2337/diacare.22.4.623 | author1 = The Diabetes Prevention Program Research Group }}</ref><ref name=NEJM>{{cite journal | vauthors = Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM | title = Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin | journal = The New England Journal of Medicine | volume = 346 | issue = 6 | pages = 393–403 | date = February 2002 | pmid = 11832527 | pmc = 1370926 | doi = 10.1056/NEJMoa012512 }}</ref> This called into question the efficacy of the monitoring strategy. The NIH responded on June 4 by dropping troglitazone from the study.<ref name=Willman /><ref name=Gale>{{cite journal | vauthors = Gale EA | title = Troglitazone: the lesson that nobody learned? | journal = Diabetologia | volume = 49 | issue = 1 | pages = 1–6 | date = January 2006 | pmid = 16362281 | doi = 10.1007/s00125-005-0074-6 | doi-access = free }}</ref> 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.<ref name=Willman /><ref name=LATimes2>{{cite news| vauthors = Willman D |title=FDA's Approval and Delay in Withdrawing Rezulin Probed|url=http://www.pulitzer.org/archives/6486|access-date=12 December 2012|newspaper=The Los Angeles Times|date=16 August 2000}}</ref> 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."<ref name=LATimes3>{{cite news| vauthors = Willman D |title=Fears Grow Over Delay in Removing Rezulin|url=http://www.pulitzer.org/archives/6483|access-date=12 December 2012|newspaper=The Los Angeles Times|date=10 March 2000}}</ref>

On March 21, 2000, the FDA withdrew the drug from the market.<ref name=FDAalert>{{cite web |title=2000 Safety Alerts for Human Medical Products|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm173081.htm|archive-url=https://web.archive.org/web/20090810042743/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm173081.htm|url-status=dead|archive-date=August 10, 2009|publisher=U.S. Food and Drug Administration|access-date=12 December 2012}}</ref> 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.<ref name=LATimes /><ref>{{cite news| vauthors = Willman D |title=Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal|url=https://www.latimes.com/archives/la-xpm-2000-mar-17-mn-9908-story.html|newspaper=Los Angeles Times|date=March 17, 2000}}</ref> 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.<ref name=LATimes2 /> The drug cost $1,400 a year per patient in 1998.<ref name=Fisher /> [[Pfizer]], which had acquired Warner-Lambert in February 2000, reported the withdrawal of Rezulin cost $136 million.<ref name=Pfizer>{{cite web |title=Pfizer Annual Report 2001|url=http://people.stern.nyu.edu/jbilders/Pdf/pfizer2001ar.pdf|publisher=Pfizer|access-date=12 December 2012}}</ref>

== Mechanisms of hepatotoxicity ==
Since the withdrawal in 2000, mechanisms of troglitazone [[hepatotoxicity]] have been extensively studied using a variety of ''[[in vivo]]'',<ref name=":0">{{cite journal | vauthors = Kassahun K, Pearson PG, Tang W, McIntosh I, Leung K, Elmore C, Dean D, Wang R, Doss G, Baillie TA | display-authors = 6 | title = 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 | journal = Chemical Research in Toxicology | volume = 14 | issue = 1 | pages = 62–70 | date = January 2001 | pmid = 11170509 | doi = 10.1021/tx000180q }}</ref> ''[[in vitro]]'',<ref>{{cite journal | vauthors = Funk C, Ponelle C, Scheuermann G, Pantze M | title = 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 | journal = Molecular Pharmacology | volume = 59 | issue = 3 | pages = 627–635 | date = March 2001 | pmid = 11179459 | doi = 10.1124/mol.59.3.627 }}</ref> and computational methods.<ref name=":1">{{cite journal | vauthors = Dixit VA, Bharatam PV | title = Toxic metabolite formation from Troglitazone (TGZ): new insights from a DFT study | journal = Chemical Research in Toxicology | volume = 24 | issue = 7 | pages = 1113–1122 | date = July 2011 | pmid = 21657230 | doi = 10.1021/tx200110h }}</ref>  These studies have suggested that hepatotoxicity of troglitazone results from a combination of [[Metabolism|metabolic]] and nonmetabolic factors.<ref>{{cite journal | vauthors = Masubuchi Y | title = Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review | journal = Drug Metabolism and Pharmacokinetics | volume = 21 | issue = 5 | pages = 347–356 | date = October 2006 | pmid = 17072088 | doi = 10.2133/dmpk.21.347 | doi-access = free }}</ref>  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]] [[Quinone methide|methide]] reactive metabolites were proposed to be formed by metabolic oxidation of the [[hydroxy group]] (OH group) of the chromane ring.<ref name=":0" />   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 group]]s (CH<sub>3</sub> groups) ortho to the OH group of the chromane ring.<ref name=":1" />  This understanding has been recently used in the design of novel troglitazone derivatives with [[antiproliferative]] activity in [[breast cancer]] [[cell lines]].<ref>{{cite journal | vauthors = Salamone S, Colin C, Grillier-Vuissoz I, Kuntz S, Mazerbourg S, Flament S, Martin H, Richert L, Chapleur Y, Boisbrun M | display-authors = 6 | title = Synthesis of new troglitazone derivatives: anti-proliferative activity in breast cancer cell lines and preliminary toxicological study | journal = European Journal of Medicinal Chemistry | volume = 51 | pages = 206–215 | date = May 2012 | pmid = 22409968 | doi = 10.1016/j.ejmech.2012.02.044 }}</ref>

==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.<ref>{{cite news| vauthors = Feeley J |title=Pfizer Ends Rezulin Cases With $205 Million to Spare|url=https://www.bloomberg.com/apps/news?pid=newsarchive&sid=act0akCefQwo|access-date=6 April 2014|newspaper=Bloomberg|date=March 31, 2009}}</ref>

== References ==
{{Reflist|2}}

== External links ==
* {{cite web | url = http://www.diabetesmonitor.com/rezulin.htm | archive-url = https://web.archive.org/web/20010811135555/http://www.diabetesmonitor.com/rezulin.htm | archive-date = 11 August 2001 | title = Troglitazone | work = Diabetes Monitor | date = 28 March 2000 }}
* {{cite web | url = http://www.rxlist.com/cgi/generic/troglitazone.htm | archive-url = https://web.archive.org/web/20040405083219/http://www.rxlist.com/cgi/generic/troglitazone.htm | archive-date = 5 April 2004 | work = RxList | title = Troglitazone }}

{{Oral hypoglycemics}}
{{PPAR modulators}}
{{Xenobiotic-sensing receptor modulators}}

[[Category:3β-Hydroxysteroid dehydrogenase inhibitors]]
[[Category:Aromatase inhibitors]]
[[Category:Chromanes]]
[[Category:CYP3A4 inducers]]
[[Category:Drugs developed by Pfizer]]
[[Category:CYP17A1 inhibitors]]
[[Category:Hepatotoxins]]
[[Category:Phenol ethers]]
[[Category:Thiazolidinediones]]
[[Category:Withdrawn drugs]]