Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics*

Abstract

Aims The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple‐dose regimens. Methods Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100 mg three times daily and 12.5, 50, 200 mg three times daily, respectively. Plasma levels of levodopa, 3‐O‐methyldopa (3‐OMD) and 3,4‐dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250 mg levodopa. Results Endogenous concentrations of levodopa and 3‐OMD increased dose‐dependently (from 8 up to 52 μg l−1 and from 0.02 up to 0.50 mg l−1, respectively, at doses of 200 mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration‐time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9 mg l−1 h at benserazide doses of 100–200 mg three times daily. Benserazide caused a dose‐dependent increase in the AUC of 3‐OMD from 7.4 to 106 mg l−1 h at doses of 200 mg. Formation of DOPAC was dose‐dependently suppressed, with benserazide 5 mg three times daily already halving its AUC. Conclusions The benserazide‐dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.

Investigation of the impact of sarizotan on the pharmacokinetics of levodopa

“…Levodopa PK in combination with dopa-decarboxylase inhibitors are characterized by variable C max values occurring at 0.5-2 h after drug administration and an apparent t 1/2 of approximately 1.7 h. In the absorption phase, the PK of levodopa were slightly different depending on the formulation of levodopa. The levodopa PK characteristics reported here are in accordance with literature data [8,9,13,14].…”

“…cardiovascular or gastrointestinal effects. The effect of dopa-decarboxylase inhibitors on the PK of levodopa has been reported previously [13][14][15]. As sarizotan was planned to be administered concomitantly with these established antiparkinsonian medications, this study was designed to investigate the effect of sarizotan on the PK of levodopa in plasma, when levodopa was administered in fixed combination with either carbidopa or benserazide.…”

Levodopa delivery systems for the treatment of Parkinson's disease: An overview

“…The effect of food on IEDD activity seemed to be much greater. Indeed, benserazide is less active than carbidopa in inhibiting the peripheral decarboxylase when given concomitantly with food; the inhibition property of carbidopa does not seem to be dependent on food intake (Dingemanse et al, 1997).…”

Levodopa reduces risk factors for vascular disease in parkinsonian patients

“…On the face of it therefore the metabolic effects of dopamine should be mainly due to its central actions [8]. However extracerebral effects of dopamine are also likely because gastrointestinal mucosa contains abundant decarboxylase activity, and peripheral decarboxylase inhibitor does not completely inhibit peripheral transformation of levodopa to dopamine [9].…”