Catechol-O-methyl
transferase (COMT) inhibitors,
entacapone and
tolcapone, are used as an adjunctive treatment to
L-dopa in
Parkinson's disease. Based on their
catechol structure, both inhibitors are potential
uncoupling agents, but only
tolcapone shows this effect in vitro at clinically relevant concentrations. This study was designed to evaluate the direct uncoupling effects of the two COMT inhibitors in vitro and in vivo. In isolated rat liver mitochondria,
entacapone had no effect on the membrane potential at therapeutical concentrations, but both
tolcapone and the reference compound
2,4-dinitrophenol disrupted the potential at low microM concentrations. Since protein binding is speculated to decrease the uncoupling effects in vivo, the COMT inhibitory effect of
entacapone and
tolcapone as a surrogate for the overall activity of these inhibitors was evaluated in vitro with or without serum. The COMT inhibitory activity of
entacapone was reduced to half, while
tolcapone had only about 1/10 of its activity left in the presence of serum. Further, uncoupling is known to induce an increase in the body temperature in vivo, and these effects were evaluated in the rat by a possible hyperthermic response to the treatment with
entacapone or
tolcapone in combination with
L-dopa (10 mg/kg) and
carbidopa (20 mg/kg). This combination with
entacapone (400 mg/kg) had no effect on the rectal body temperature. In contrast,
tolcapone (50 mg/kg) caused an elevation in the body temperature together with
L-dopa and
carbidopa (P < 0.01). Both in vitro and in vivo results indicate that
entacapone does not impair energy metabolism related to uncoupling of oxidative phosphorylation.