Abstract
Troglitazone is a new thiazolidinedione oral antidiabetic agent approved for use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Food increases the absorption by 30 to 80%. The pharmacokinetics of troglitazone are linear over the clinical dosage range of 200 to 600mg once daily. The mean elimination half-life ranges from 7.6 to 24 hours, which facilitates 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) and quinone metabolite (M3), respectively. M1 and M3 are the major metabolites in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacokinetics of troglitazone and its 2 major metabolites. In patients with hepatic 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%. Troglitazone 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 of the oral contraceptive hormones ethinylestradiol, norethindrone and levonorgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, glibenclamide (glyburide) or paracetamol (acetaminophen). There is no pharmacodynamic interaction between troglitazone and warfarin or alcohol (ethanol).
Pharmacodynamic modelling showed that improvement in fasting glucose and triglyceride levels increased with dose from 200 to 600mg. Knowledge of systemic troglitazone exposure within a dose group does not improve the prediction of glucose lowering response or adverse effects beyond those based on the administered dose.
Similar content being viewed by others
References
Schwartz S, Raskin P, Fonseca V, et al. Effect of troglitazone in insulin-treated patients with type 2 diabetes mellitus. N Engl JMed 1998; 338: 861–6.
Maggs DG, Buchanan TA, Burant CF, et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128: 176–85.
Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type 2 diabetes mellitus. N Engl J Med 1998; 338: 867–72.
Kumar S, Boulton AJM, Beck-Nielsen H, et al. Troglitazone, an insulin action enhancer, improves metabolic control in type 2 diabetes patients. Diabetologia 1996; 39: 701–9.
Buse JB, Gumbiner B, Mathias NP, et al. Troglitazone use in insulin-treated type 2 diabetic patients. Diabetes Care 1998; 21: 1455–61.
Horton ES, Whitehouse F, Ghazzi MN, et al. Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. Diabetes Care 1998; 21: 1462–9.
Fonseca VA, Valiquett TR, Huang SM, et al. Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: A randomized, controlled study. J Clin Endocrinol Metab 1998; 83: 3169–76.
Nolan JJ, Ludvik B, Beerdsen P, et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994; 331: 1188–93.
Cavaghan MK, Ehrmann DA, Byrne MM, et al. Treatment with oral antidiabetic agent troglitazone improves β cell responses to glucose in subjects with impaired glucose tolerance. J Clin Invest 1997; 100: 530–7.
Antonucci T, McLain R, Whitcomb R, et al. Impaired glucose tolerance is normalized by treatment with the thiazolidi-nedione, troglitazone. Diabetes Care 1997; 20: 188–93.
Fujiwara T, Yoshioka T, Ushiyama I, et al. Characterisation of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 1988; 37: 1549–58.
Horikoshi H, Fujiwara T, Yoshioka S, et al. Pharmacological characteristics of new antidiabetic agent CS-045 in diabetic animals. In: Shafrir H, editor. Frontiers in diabetes research: lessons from animal diabetes III. London: Smith-Gordon, 1990.
Lee MK, Olefsky JM. Acute effects of troglitazone on in vivo insulin action in normal rats. Metabolism 1995; 44: 1166–9.
Lee MK, Miles PDG, Khoursheed M, et al. Metabolic effects of troglitazone on fructose-induced insulin resistance in the rat. Diabetes 1994; 43: 1435–9.
Fujiwara T, Wada M, Fukuda K, et al. Characterisation of CS-045, a new oral antidiabetic agent: II. Effects on glycemic control and pancreatic islet structure at a late stage of the diabetic syndrome in C57BL/KsJ-db/db mice. Metabolism 1991; 40 (11): 1213–8.
Tominaga M, Igarashi M, Daimon M, et al. Thiazolidinediones (AD-4833 and CS-045) improve hepatic insulin resistance in streptozotocin-induced diabetic rats. Endocr J 1993; 40: 343–9.
Balcom JH, Sindelar D, Scott M, et al. Troglitazone (CI-991) does not sensitise the normal dog liver to insulin action [abstract 133]. Diabetes 1994; 43 Suppl. 1: 43A.
Fujiwara T, Okuno A, Yoshioka S, et al. Suppression of hepatic gluconeogenesis in long-term troglitazone treated diabetic KK and C57BL/KsJ-bd/db mice. Metabolism 1995; 44 (4): 486–90.
Murano K, Inoue Y, Emoto M, et al. CS-045, a new oral anti-diabetic agent, stimulates fructose-2,6-bisphosphate production in rat hepatocytes. Eur J Pharmacol 1994; 254: 257–62.
Lenhard JM, Kliewer SA, Paulik MA, et al. Effects of troglitazone and metformin on glucose and lipid metabolism. Biochem Pharmacol 1997; 54: 801–8.
Willson TM, Cobb JE, Cowan DJ, et al. The structure-activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem 1996; 39: 665–8.
Lehmann JM, Moore LB, Smith-Oliver TA, et al. An anti-diabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor y (PPARy). J Biol Chem 1995; 270 (22): 12953–6.
Vidal-Puig A, Jimenez-Linan M, Lowell BB, et al. Regulation of PPARγ gene expression by nutrition and obesity in rodents. J Clin Invest 1996; 97: 2553–61.
The absolute bioavailability of troglitazone. GlaxoWellcome Co., 1997. (Data on file).
Young MA, Lettis S, Eastmond R. Improvement in the gastrointestinal absorption of troglitazone when taken with, or shortly after, food. Br J Clin Pharmacol 1998; 45: 31–5.
A pilot single-dose food effectandintrasubjectvariability study of CI-991 200-mg tablets. Parke-Davis Pharmaceutical Research, 1994. (Data on file).
A pilot single-dose pharmacokinetic study comparing the bioavailability of Parke-Davis troglitazone tablets, Parke-Davis troglitazone soft gelatin capsules, and Sankyo troglitazone tablets. Parke-Davis Pharmaceutical Research, 1993. (Data on file).
Knowlton PW, Loi CM, Vassos AB, et al. Pharmacokinetics of troglitazone in patients with renal insufficiency. Clin Drug Invest 1999; 17: 127–36.
Ott P, Ranek L, Young MA. Pharmacokinetics of troglitazone a PPAR gamma agonist, in patients with hepatic insufficiency. Eur J Clin Pharmacol 1998; 54: 567–71.
Bayesian estimation of troglitazone pharmacokinetic parameters following intravenous and oral administration. Parke-Davis Pharmaceutical Research, 1997. (Data on file).
Izumi T, Enomoto S, Hosiyama K, et al. Prediction of the human pharmacokinetics of troglitazone, a new and extensively metabolized antidiabetic agent, after oral administration, with an animal scale-up approach. J Pharmacol Exp Ther 1996; 277: 1630–41.
Kawai K, Kawasaki-Tokui Y, Odaka T, et al. Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice, and dogs. Arzneimettel Forschung Drug Res 1997; 47: 356–68.
Rezulin product labelling. Morris Plains (NJ): Warner-Lambert Company, 1999.
Loi CM, Alvey CW, Vassos AB, et al. Steady-state pharmacokinetics and dose proportionality of troglitazone and its metabolites. J Clin Pharmacol. In press.
CI-991: In vitro metabolism and stability. Parke-Davis Pharmaceutical Research, 1995. (Data on file).
Loi CM, Randinitis EJ, Vassos AB, et al. Lack of effect of type 2 diabetes on the pharmacokinetics of troglitazone in a multiple-dose study. J Clin Pharmacol 1997; 37: 1114–20.
Young MA, Williams ZV, Eastmond R. Similar pharmacokinetics of troglitazone in young and elderly subjects [abstract]. Diabetologia 1996; 39 Suppl. 1: A233.
An open-label, positive-controlled, 48-week, multicenter study of troglitazone in patients with noninsulin dependent diabetes mellitus to assess potential effects on cardiac mass and function. Parke-Davis Pharmaceutical Research, 1993. (Data on file).
Ghazzi MN, Perez JE, Antonucci TK, et al. Cardiac and glycemic benefits of troglitazone treatment in type 2 diabetes. Diabetes 1997; 46: 433–9.
Stereoselective pharmacokinetics of troglitazone in healthy volunteers and NIDDM patients. GlaxoWellcome Co., 1996. (Data on file).
Loi CM, Alvey CW, Randinitis EJ, et al. Meta-analysis of steady-state pharmacokinetics of troglitazone. J Clin Pharmacol 1997; 37: 1038–47.
Investigation of the metabolism in vitro of GR921 32X (CI-991) in the presence of varying concentrations of ethanol. GlaxoWellcome Co., 1994. (Data on file).
Investigation of the in vitro protein binding of [14C]GR92132 to human serum albumin alone and in the presence of various drugs. GlaxoWellcome Co., 1993. (Data on file).
Young MA, Lettis S, Eastmond R. Coadministration of acetaminophen and troglitazone: pharmacokinetics and safety. J Clin Pharmacol 1998; 38: 819–24.
Loi CM, Stern R, Abel R, et al. Effect of troglitazone on pharmacokinetics and pharmacodynamics of atorvastatin [abstract]. Clin Pharmacol Ther 1999; 65: 186.
Young MA, Lettis S, Eastmond R. Concomitant administration of cholestyramine influences the absorption of troglitazone. Br J Clin Pharmacol 1998; 45: 37–40.
Kaplan B, Friedman G, Jacobs M, et al. Potential interaction of troglitazone and cyclosporine. Transplantation 1998; 65 (10): 1399–400.
Burgess SJ, Singer GG, Brennan DC. Effect of troglitazone on cyclosporine whole blood levels [abstract]. Transplantation 1998; 66 (2): 272.
Loi CM, Knowlton PW, Stern R, et al. Effect of troglitazone on steady-state pharmacokinetics of digoxin. J Clin Pharmacol 1998; 38: 178–83.
Foot E, Eastmond R. Good metabolic and safety profile of troglitazone alone and following alcohol in type 2 diabetes subjects. Diabetes Res Clin Pract 1997; 38: 41–51.
Loi CM, Koup JR, Vassos AB, et al. Effect of troglitazone on fexofenadine pharmacokinetics [abstract]. Clin Pharmacol Ther 1999; 65: 186.
Interaction of troglitazone and glibenclamide in NIDDM patients. Sankyo Europe Co., 1995. (Data on file).
Foot EA, Patel J, Williams ZV, et al. Improved metabolic control by addition of troglitazone to glibenclamide therapy in noninsulin-dependent diabetics [abstract]. Diabetologia 1995; 38 Suppl. 1: A44.
A study to investigate the safety and tolerability of the addition of troglitazone to the normal metformin therapy of type II diabetics. GlaxoWellcome Co., 1998. (Data on file).
Loi CM, Stern R, Koup JR, et al. Effect of troglitazone on the pharmacokinetics of an oral contraceptive agent. J Clin Pharmacol 1999; 39: 410–7.
A study to investigate the pharmacokinetic interaction of troglitazone and the oral contraceptive, Microgynon 30®. GlaxoWellcome Co., 1997. (Data on file).
Loi CM, Stern R, Vassos AB, et al. Effect of troglitazone on terfenadine pharmcokinetics [abstract]. Clin Pharmacol Ther 1998; 63: 228.
Loi CM, Knowlton P, Stern R, et al. Effect of troglitazone on terfenadine pharmacokinetics when dosed 4 hours apart [abstract]. Clin Pharmacol Ther 1998; 63: 229.
A study to determine the effect of multiple-dose troglitazone (CI-991) administration on anticoagulant activity in patients maintained on warfarin. Parke-Davis Pharmaceutical Research, 1996. (Data on file).
Koup JR, Anderson G, Loi CM. Effect of troglitazone on urinary excretion of Cortisol and 6β-hydroxycortisol. J Clin Pharmacol 1998; 38: 815–8.
Valiquett TR, Balagtas CC, Whitcomb RW, et al. Troglitazone dose-response study in patients with noninsulin dependent diabetes [abstract]. Clin Res 1994; 42: 400A.
Relationship between troglitazone pharmacokinetics and glucose pharmacodynamics in a 12-week, double-blind, placebo-controlled, multicenter, dose-response study of troglitazone in patients with noninsulin-dependent diabetes mellitus. Parke-Davis Pharmaceutical Research, 1996. (Data on file).
Leutenegger M, Sacca L, Alderton C, et al. Double-masked, placebo-controlled, dose-ranging study of troglitazone 10 to 200 mg once daily in noninsulin-dependent diabetes mellitus. Curr Ther Res 1997; 58 (7): 403–16.
Young MA, Eckland DJA, Eastmond R, et al. Establishing the dose response curve for metabolic control with troglitazone, an insulin action enhancer, in type 2 diabetes patients. Ann Med 1998; 30: 206–12.
Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone. N Engl J Med 1998; 338: 916–7.
Neuschwander-Tetri BA, Isley WL, Oki JC, et al. Troglitazoneinduced hepatic failure leading to liver transplantation. Ann Intern Med 1998; 129: 38–41.
Gitlin N, Julie NL, Spurr CL, et al. Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med 1998; 129: 36–8.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Loi, CM., Young, M., Randinitis, E. et al. Clinical Pharmacokinetics of Troglitazone. Clin Pharmacokinet 37, 91–104 (1999). https://doi.org/10.2165/00003088-199937020-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199937020-00001