Pharmacokinetics of troglitazone, a PPAR-γ agonist, in patients with hepatic insufficiency

Abstract

Objective: Troglitazone is an agonist of the peroxisome proliferator-activated receptor-γ (PPAR-γ), which has been shown to improve the metabolic control of type 2 diabetes. Troglitazone undergoes hepatic metabolism to an inactive sulphate conjugate and an oxidative quinone metabolite with minor activity. The objective of this study was to compare the pharmacokinetics of troglitazone in patients with hepatic insufficiency and normal subjects.

Methods: Three groups of eight subjects with normal liver function and moderate or severe hepatic impairment (Pugh-Child classification) completed this open study. Subjects received a single 400-mg dose of troglitazone 30 min after breakfast. Plasma concentrations of troglitazone and its metabolites were measured and standard pharmacokinetic parameters derived.

Results: A 46% increase in area under the plasma concentration-time curve (AUC_last) was observed for troglitazone, together with a 154% increase for the quinone metabolite in the patients with moderate hepatic impairment compared with normal subjects, but these did not reach statistical significance. Corresponding increases of 18% and 53% in the severe group also failed to reach statistical significance. For the sulphate conjugate, the AUC_last values for both moderate and severe hepatic impairment were in the order of fourfold higher than those in the normal group. There were reductions in the maximum observed plasma concentration (C_max) of troglitazone to 61% of the normal group in the severe group for troglitazone, and twofold increases in sulphate metabolite C_max in the moderate and severe groups. There was an approximately threefold increase in the half-life of the sulphate conjugate in subjects with both moderate and severe impairment of liver function compared with normal individuals. First times to maximum concentrations of troglitazone, its sulphate conjugate and the quinone metabolite were significantly longer in all severely impaired subjects compared with those with normal hepatic function, although the range was wide in all cases. Plasma protein binding was high in all subjects measured (mean unbound fraction range 0.7–5.1%), but there were insufficient samples to compare across groups.

Conclusion: The formation of metabolites of troglitazone following a single dose is not impaired in the presence of reduced liver function although the capacity to eliminate the metabolites is altered. The clinical significance of the effect of liver disease on the conjugates is not clear.