PHARMACOKINETICS OF TROGLITAZONE, A PPAR-GAMMA AGONIST, IN PATIENTS WITH HEPATIC INSUFFICIENCY

Objective: Troglitazone is an agonist of the peroxisome proliferator-a ctivated receptor-gamma (PPAR-gamma), which has been shown to improve the metabolic control of type 2 diabetes. Troglitazone undergoes hepat ic metabolism to an inactive sulphate conjugate and an oxidative quino ne 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 subj ects with normal liver function and moderate or severe hepatic impairm ent (Pugh-Child classification) completed this open study. Subjects re ceived a single 400-mg dose of troglitazone 30 min after breakfast. Pl asma concentrations of troglitazone and its metabolites were measured and standard pharmacokinetic parameters derived. Results: A 46% increa se in area under the plasma concentration-time curve (AUC(last)) was o bserved for troglitazone, together with a 154% increase for the quinon e metabolite in the patients with moderate hepatic impairment compared with normal subjects, but these did not reach statistical significanc e. Corresponding increases of 18% and 53% in the severe group also fai led 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 tro glitazone, and twofold increases in sulphate metabolite C-max in the m oderate and severe groups. There was an approximately threefold increa se in the half-life of the sulphate conjugate in subjects with both mo derate and severe impairment of liver function compared with normal in dividuals. First times to maximum concentrations of troglitazone, its sulphate conjugate and the quinone metabolite were significantly longe r in all severely impaired subjects compared with those with normal he patic function, although the range was wide in all cases. Plasma prote in binding was high in all subjects measured (mean unbound fraction ra nge 0.7-5.1%), but there were insufficient samples to compare across g roups. Conclusion: The formation of metabolites of troglitazone follow ing a single dose is not impaired in the presence of reduced liver fun ction although the capacity to eliminate the metabolites is altered. T he clinical significance of the effect of liver disease on the conjuga tes is not clear.