Troglitazone

(BAN, USAN, rINN)
Troglitazone Chemical formula
Synonyms: CI-991; CS-045; GR-92132X; Troglitazona; Troglitazonum. (±)allrac-5-{p-[(6-Hydroxy-2,5,7,8-tetramethyl-2-chromanyl)methoxy]benzyl}-2,4-thiazolidinedione.
Cyrillic synonym: Троглитазон.

💊 Chemical information

Chemical formula: C24H27NO5S = 441.5.
CAS — 97322-87-7.
ATC — A10BG01.
ATC Vet — QA10BG01.

💊 Adverse Effects and Precautions

Troglitazone has been associated with severe hepatic reactions, sometimes fatal, which has led to its withdrawal in most countries. Regular monitoring of liver function during therapy, and withdrawal of the drug in any patient who develops jaundice or signs of liver dysfunction, is required. It should not be given to patients with pre-existing moderate or severe elevations of liver enzyme values, or active liver disease. Increased plasma volume has been reported in healthy subjects given troglitazone: it should be used with caution in patients with heart failure. Other adverse effects reported in patients receiving troglitazone include dizziness, headache, fatigue, musculoskeletal pain, and nausea and vomiting. There is no evidence of hypoglycaemia associated with the use of troglitazone alone.

Effects on the liver.

The UK CSM1 was aware of over 130 cases of hepatic reactions to troglitazone worldwide as of December 1997, although only 1 had been in the UK. There had been 6 deaths. The average time to the onset of the reaction was 3 months, but the frequency of these reactions, and the existence of risk factors predisposing to them, were unclear. The manufacturers had voluntarily withdrawn the drug in the UK. The US manufacturer and the FDA recommended2 a schedule for routine monitoring of liver function in November 1997 and revised this again in December 1997. It was estimated that 2% of patients treated with troglitazone would have elevated liver enzyme values necessitating discontinuation of the drug. The FDA3had received 560 reports of troglitazone-associated hepatotoxicity by June 1998. There were 24 cases of hepatic failure which were likely to have been caused by the drug; 21 patients died and 3 patients received transplants. More intensive liver function monitoring recommendations were made by the US manufacturer again in July 1998 and in June 1999. Subsequently the manufacturer withdrew the drug in Australia, Japan, and the USA in March 2000. The clinical details of 94 cases of liver failure associated with troglitazone, which were reported to the FDA, have been reviewed.4
1. CSM/MCA. Troglitazone (Romozin) withdrawn. Current Problems 1997; 23: 13. Also available at: http://www.mhra.gov.uk/ home/idcplg?IdcService=GET_FILE&dDocName= CON2023238&RevisionSelectionMethod=LatestReleased (accessed 02/06/06
2. Anonymous. Troglitazone and liver injury. WHO Drug Inf 1998; 12: 13
3. Misbin RI. Troglitazone-associated hepatic failure. Ann Intern Med 1999; 130: 330
4. Graham DJ, et al. Troglitazone-induced liver failure: a case study. Am J Med 2003; 114: 299–306.

💊 Interactions

Troglitazone may enhance the hypoglycaemic effects of sulfonylureas; dosage adjustment may be necessary. There is a possibility that troglitazone may enhance the metabolism of drugs metabolised by cytochrome P450 isoenzyme CYP3A4, including some oral contraceptives and terfenadine.

Ciclosporin.

For the effect of troglitazone on blood concentrations of ciclosporin see Hypoglycaemic Drugs.

Colestyramine.

Colestyramine markedly impaired the absorption of troglitazone.1
1. Young MA, et al. Concomitant administration of cholestyramine influences the absorption of troglitazone. Br J Clin Pharmacol 1998; 45: 37–40.

💊 Pharmacokinetics

Troglitazone is rapidly absorbed after oral doses, with peak plasma concentrations 1 to 3 hours after a dose. Bioavailability is about 53%; absorption is markedly increased in the presence of food. In the body, troglitazone is more than 99% bound to plasma albumin. It is extensively metabolised in the liver and excreted largely in faeces as metabolites; small amounts of metabolites are excreted in urine. Plasma elimination half-life ranges from 10 to 39 hours.
1. Loi C-M, et al. Clinical pharmacokinetics of troglitazone. Clin Pharmacokinet 1999; 37: 91–104.

💊 Uses and Administration

Troglitazone is a thiazolidinedione oral antidiabetic. It has been given orally for the treatment of type 2 diabetes mellitus although as mentioned above it has been withdrawn in most countries owing to hepatotoxicity.
1. Plosker GL, Faulds D. Troglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 1999; 57: 409–38
2. Parulkar AA, et al. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 2001; 134: 61–71.

💊 Preparations

Proprietary Preparations

Mex.: Rezulin†.
Published December 04, 2018.