troglitazone (Rezulin)

Introduction

Tradename: Rezulin.

FDA HAS WITHDRAWN TROGLITAZONE FROM THE US MARKET (3/2000).

Indications

• treatment of diabetes mellitus type 2 with poor control despite 30 or more units of insulin/day
• treatment of diabetes mellitus type 2 in conjunction with a sulfonylurea
• initial monotherapy as an adjunct to diet & exercise to lower blood glucose in patients with type 2 diabetes

The 1st of a new class of thiazolidinedione derivatives for treatment of non-insulin dependent diabetes & in patients taking more than 30 units of insulin/day with Hgb A1c > 8.5%.

Contraindications

• class III or class IV heart failure
• pregnancy
• hepatic dysfunction

pregnancy category = b

safety in lactation = -

Dosage

• start 200 mg PO QD
• increase dose in 4 weeks if response is inadequate
• usual dose is 400 mg QD
• maximum: 600 mg PO QD
• take with food

Tabs: 200 & 400 mg.

Pharmacokinetics

• extensively metabolized in the liver
• inhibits cyt P450 1A1, 1A2, 2A6, 2B6, 2D6, 2E1 & 3A4
• bioavailability: absolute
• elimination 1/2life 16-34 hours
• time to peak plasma levels is 2-3 hours
• elimination: 85% in feces, 3% in urine
• maximum effect is seen after 12 weeks of therapy
• discontinue patients not responding on 600 mg/day after 12 weeks
• 20-50% of patients will not respond to therapy with troglitazone

elimination via liver

1/2life = 16-34 hours

Monitor

• liver function tests at start & monthly for 1st 6 months, every other month for the following 6 months & periodically thereafter
• blood glucose daily during dose titration

• monitor with thiazolidinediones (glitazones)

Adverse effects

• common (> 10%)
  • headache, apin, infection
• less common (1-10%)
  • peripheral edema, dizziness, nausea, diarrhea, pharyngitis, urinary tract infection, neck pain, weakness, rhinitis, hepatoxicity*
• other
  • mild reversible increases in serum aminotransferases *Note: approved on a fast track by the FDA.
    • In one year, 33 deaths occurred from hepatotoxixity of troglitazone
  • jaundice
  • 6-8% increase in plasma volume
  • cardiac hypertrophy in laboratory animals

• drug adverse effects of thiazolidinediones
• drug adverse effects of hypoglycemic agents

Drug interactions

• cholestyramine decreases absorbtion of troglitazone. They should be taken at different times of the day
• Troglitazone lowers serum concentrations of oral contraceptives & Terfenadine (Seldane), which are also metabolized by CYP3A4
• coadministration of troglitazone with glyburide may result in hypoglycemia

• drug interaction(s) of fluoroquinolones with hypoglycemic agents

Mechanism of action

• troglitazone decreases insulin resistance through binding to nuclear peroxisome proliferator receptors involved in transcription of insulin-responsive genes.
• in the presence of insulin, troglitazone has the following properties:
  • decreases gluconeogenesis & triglyceride synthesis in liver
  • increases glucose uptake & utilization in skeletal muscle
  • increases glucose uptake & decrease fatty output in adipose tissue
• has no known effect on insulin secretion

More general terms

• thiazolidinedione; glitazone; TZD
• peroxisome proliferator; PPAR agonist; PPAR gamma agonist

Additional terms

• peroxisome proliferator-activated receptor gamma; PPAR-gamma; nuclear receptor subfamily 1 group C member 3 (PPARG, NR1C3)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5591