Clinical pharmacokinetics of troglitazone

Troglitazone is a new thiazolidinedione oral antidiabetic agent approved fo r use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Fo od increases the absorption by 30 to 80%. The pharmacokinetics of troglitaz one are linear over the clinical dosage range of 200 to 600mg once daily. T he mean elimination half-life ranges from 7.6 to 24 hours, which facilitate s a once daily administration regimen. The pharmacokinetics of troglitazone are similar between patients with type 2 diabetes and healthy individuals. In humans, troglitazone undergoes metabolism by sulfation, glucuronidation and oxidation to form a sulfate conjugate(M1), glucuronide conjugate (M2) a nd quinone metabolite (M3), respectively. hll and M3 are the major metaboli tes in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacok inetics of troglitazone and its 2 major metabolites. In patients with hepat ic impairment the plasma concentrations of troglitazone, M1 and M3 increase by 30%, 4-fold, and 2-fold, respectively. Cholestyramine decreases the absorption of troglitazone by 70%. Troglitazon e may enhance the activities of cytochrome P450 (CYP) 3A and/or transporter (s) thereby reducing the plasma concentrations of terfenadine, cyclosporin, atorvastatin and fexofenadine. It also reduces the plasma concentrations o f the oral contraceptive hormones ethinylestradiol, norethindrone and levon orgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, gli benclamide (glyburide) or paracetamol (acetaminophen). There is no pharmaco dynamic interaction between troglitazone and warfarin or alcohol (ethanol). Pharmacodynamic modelling showed that improvement in fasting glucose and tr iglyceride levels increased with dose from 200 to 600mg. Knowledge of syste mic troglitazone exposure within a dose group does not improve the predicti on of glucose lowering response or adverse effects beyond those based on th e administered dose.