Lack of Effect of Type II Diabetes on the Pharmacokinetics of Troglitazone in a Multiple-Dose Study

Abstract

Twelve patients with type II diabetes and 12 age‐, weight‐, and gender‐matched healthy subjects participated in a study comparing the pharmacokinetics of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone) after oral administration of 400 mg of troglitazone every morning for 15 days. Serial plasma samples collected after the dose on days 1 and 15 were analyzed for troglitazone, metabolite 1, and metabolite 3 using a validated HPLC method. Steady‐state plasma concentrations of troglitazone and its metabolites were achieved by the fifth day of troglitazone administration in both groups. Mean day 15 C_max, t_max, AUC_0–24, and Cl/F values of troglitazone were 1.54 μg/mL, 3.25 hours, 15.6 μg · hr/mL, and 461 mL/min, respectively, in patients with type II diabetes. Corresponding parameter values were 1.42 μg/mL, 2.63 hours, 12.5 μg · hr/mL, and 558 mL/min, respectively, in healthy subjects. Elimination t1/2 was approximately 24 hours in both groups. Mean day 15 pharmacokinetic parameter values for metabolite 1 and metabolite 3 were similar in the two groups. Ratio of AUC of metabolite 1 to troglitazone was 6.2 and 6.7, respectively, in patients and in healthy subjects. Ratio of AUC of metabolite 3 to troglitazone was 1.1 in both groups. Thus, steady‐state pharmacokinetics and disposition of troglitazone and its metabolites in patients with type II diabetes were similar to those in healthy subjects.