Impact of the catechol-O-methyltransferase Val158Met polymorphism on the pharmacokinetics of l-dopa and its metabolite 3-O-methyldopa in combination with entacapone

In the pharmacotherapy of patients with Parkinson’s disease (PD), entacapone reduces the peripheral metabolism of l -dopa to 3- O -methyldopa (3-OMD), thereby prolonging the half-life ( t 1/2 ) of l -dopa and increasing the area under the concentration curve (AUC). The effect of entacapone on the pharmacokinetics of l -dopa differs between patients with high-activity (H/H) and low-activity (L/L) catechol- O -methyltransferase (COMT) Val158Met polymorphisms, but the effects are unclear in heterozygous (H/L) patients. 3-OMD has a detrimental effect and results in a poor response to l -dopa treatment in patients with PD; however, the influence of this polymorphism on the production of 3-OMD remains unknown. Therefore, the present study aimed to clarify the effect of the COMT Val158Met polymorphism on the concentrations of l -dopa and 3-OMD in the presence of entacapone. We performed an open-label, single-period, single-sequence crossover study at two sites in Japan. The study included 54 Japanese patients with PD, who underwent an acute l -dopa administration test with and without 100 mg entacapone on two different days. Entacapone increased l -dopa AUC 0–infinity by 1.59 ± 0.26-fold in the H/H group, which was significantly higher than that in the H/L (1.41 ± 0.36-fold) and L/L (1.28 ± 0.21-fold) groups ( p