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

Abstract

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.

Determination of Monoamine Oxidase A and B Activity in Long-Term Treated Patients With Parkinson Disease

“…12 Thus, the individual variability of levodopa plasma bioavailability after gastrointestinal levodopa absorption may also contribute to the observed variation of peripheral MAO enzyme activity. 11 Here, we found no impact of previous levodopa intake on MAO-A enzyme activity and cannot postulate such an effect in the case of MAO-B because of the missing control group in contrast to our earlier trial. 2 A further theoretical cause may be that this phenomenon additionally at least partially results from the presence of endogenous MAO inhibitors.…”

Inhibition of catechol-O-methyltransferase modifies acute homocysteine rise during repeated levodopa application in patients with Parkinson’s disease

“…This may probably be due to higher concentrations of levodopa, respectively its derivative dopamine, in the gastrointestinal tract. Both compounds may delay gastric emptying via an amino acid-dependent feedback mechanism and thus postpone duodenal levodopa absorption further (Muller 2010b).…”

“…Nearly all investigators performed an overnight withdrawal of PD drugs before blood sampling for homocysteine determination or do not describe the modes of blood sampling in detail. Thus they do not consider that acute one time levodopa/benserazide intake increases homocysteine plasma levels dependent on the gastrointestinal absorption and subsequent plasma appearance of levodopa (Muller and Kuhn 2009;Muller 2010b). In clinical practice, levodopa/DDI is often administered several times per day in PD patients of more advanced stages particularly.…”

Drug therapy in patients with Parkinson’s disease

“…These pharmacokinetic characteristics of LD plasma behaviour in the context with EN supplementation to a LD/CD regimen was underestimated respectively not known, when STRIDE-PD was designed. However the design of STRIDE-PD did not allow prolonging of dosing intervals or dose reduction after initial EN supplementation to an existing LD/CD regimen [22,33]. …”