Objective: The pharmacokinetic profiles of troglitazone and two metabolites were evaluated following a single 400mg oral dose of troglitazone in 20 patients with various degrees of renal function.
Methods: Plasma troglitazone and metabolite concentrations were determined by high performance liquid chromatography, and troglitazone free fraction was determined by ultracentrifugation.
Results: Mean maximum plasma concentration and area under the curve for total troglitazone appeared lower in patients with severe renal impairment (SRI) compared with those with normal renal function (NRF). Troglitazone free fraction was higher in patients with SRI (4.85%) than in subjects with NRF (1.66%), producing similar exposure values for unbound troglitazone, the moiety presumed to exert the pharmacological effect. Regression analysis revealed poor correlations of creatinine clearance value with total troglitazone, unbound troglitazone, and metabolite pharmacokinetic parameter values.
Conclusion: These data indicated that renal function does not predict troglitazone pharmacokinetics and systemic exposure to unbound troglitazone is unaltered with renal impairment. Thus, troglitazone dose adjustment based on pharmacokinetics is not required in patients with renal insufficiency.
Adis International Limited Normal Renal Function Troglitazone Severe Renal Impairment Clin Drug Invest
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Ciaraldi TP, Gilmore A, Olefsky JM, et al. In vitro studies on the action of CS-045, a new antidiabetic agent. Metabolism 1990; 39: 1056–62PubMedCrossRefGoogle Scholar
Fujiwara T, Yoshioka S, Yoshioka T, et al. Characterization of new oral antidiabetic agent CS-045: studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 1988; 37: 1549–58PubMedCrossRefGoogle Scholar
Iwamoto Y, Kuzuya T, Matsuda A, et al. Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NTDDM. Diabetes Care 1991; 14: 1083–6PubMedCrossRefGoogle Scholar
Suter SL, Nolan JJ, Wallace P, et al. Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 1992; 15: 193–203PubMedCrossRefGoogle Scholar
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: 1188–93PubMedCrossRefGoogle Scholar
Loi C-M, Randinitis EJ, Vassos AB, et al. Lack of effect of type JJ diabetes on the pharmacokinetics of troglitazone in a multiple-dose study. J Clin Pharmacol 1997; 37: 1114–20PubMedGoogle Scholar
Ott P, Ranek L, Young MA. Pharmacokinetics of troglitazone, a PPAR-γ agonist, in patients with hepatic insufficiency. Eur J Pharmacol 1998; 54: 567–71CrossRefGoogle Scholar
De Fronzo RA. Diabetic nephropathy. In: Porte Jr D and Sherwin RS, editors. Ellenberg & Rifkin’s Diabetes Mellitus. 5th ed. Stamford: Appleton & Lange, 1997: 971–1008Google Scholar
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: 1630–41PubMedGoogle Scholar
Karara AH, Frye RF, Hayes PE, et al. Pharmacokinetics of abecarnil in patients with renal insufficiency. Clin Pharmacol Ther 1996; 59: 520–8PubMedCrossRefGoogle Scholar
Rogers HJ, Savitsky JP, Glenn B, et al. Kinetics of single doses of fenbufen in patients with renal insufficiency. Clin Pharmacol Ther 1981; 29: 74–80PubMedCrossRefGoogle Scholar
Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekkar Inc., 1982Google Scholar
Loi C-M, Alvey CW, Randinitis EJ, et al. Meta-analysis of steady-state pharmacokinetics of troglitazone and its metabolites. J Clin Pharmacol 1997; 37(11): 1038–47PubMedGoogle Scholar
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: 206–12PubMedCrossRefGoogle Scholar
Rezulin product labeling. Physicians Desk Reference. 52nd ed. Montvale, NJ: Medical Economics Company, 1998: 2118–21Google Scholar