The Impact of COMT-inhibition on Gastrointestinal Levodopa Absorption in Patients with Parkinson's Disease

The drug Levodopa (LD) is an efficient compound for the treatment of patients with Parkinson's disease (PD). Its short half life generates plasma behaviour of LD with peaks and troughs. Therefore, following the LD transport into the brain and the conversion to dopamine, an alternating stimulation of nigrostriatal postsynaptic dopamine receptors takes place. In the long term these fluctuations of dopamine concentrations supports onset of motor complications (MC) in PD patients. General opinion is that loss of central compensatory mechanisms of dopamine metabolism is responsible for the development of MC. However, in the periphery, LD troughs are preponderantly associated with the MC wearing off, which is the reappearance of motor symptoms with decreasing drug effect. Addition of the catechol-O-methyltransferase (COMT) inhibitor Entacapone (EN) to LD/carbidopa (CD) improved wearing off, since EN prolongs LD half life and avoids troughs. Plasma LD peaks are mostly related to the clinical manifestation of the MC dyskinesia, which appear as involuntary movements. One time addition of EN to a LD/CD formulation showed no increase of peripheral maximum LD concentration. But repeat combination of EN to each LD/CD intake elevated plasma LD bioavailability and peaks. Therefore switch from a LD/CD-to a LD/CD/EN regime may also ask for reduction of LD/CD dosing or delay of the next LD/CD intake, to avoid onset of the most common peak dose dyskinesia. In conclusion, pharmacokinetic studies on peripheral LD metabolism and mode of intake underline their importance as peripheral components for MC manifestations in PD patients.