Coadministration of acetaminophen and troglitazone: pharmacokinetics and safety

Troglitazone, a PPAR-gamma agonist, enhances the actions of insulin on muscle and liver. It is metabolized predominantly in the liver to a sulfate conjugate and a quinone metabolite. Acetaminophen also undergoes metabolism by conjugation. This three-way crossover study in 12 healthy male volunteers was conducted to investigate the effects of acetaminophen on the metabolism of troglitazone and vice versa. No statistically or clinically relevant differences in area under the concentration-time curve extrapolated to infinity (AUCinfinity) were observed for troglitazone, its quinone metabolite, or acetaminophen. A statistically significant decrease in troglitazone sulfate conjugate during administration with acetaminophen was not clinically relevant. No statistically or clinically relevant differences were observed in maximum concentration (Cmax), time to Cmax (tmax), or elimination half-life of troglitazone, its two main metabolites, and acetaminophen or in acetaminophen urinary sulfate excretion, although there was a slight decrease in acetaminophen glucuronide excretion during administration with troglitazone. Adverse events were minor and similar between treatments. These findings suggest that troglitazone and acetaminophen can be coadministered without adverse clinical consequences.