PHARMACODYNAMICS OF BENSERAZIDE ASSESSED BY ITS EFFECTS ON ENDOGENOUSAND EXOGENOUS LEVODOPA PHARMACOKINETICS

Aims The objectives of the study were to investigate the pharmacodynam ics of the peripheral decarboxylase inhibitor benserazide during multi ple-dose regimens. Methods Two groups of eight healthy male subjects w ere consecutively treated for periods of 14 days with benserazide 5, 2 5, 100 mg three times daily and 12.5, 50, 200 mg three times daily, re spectively. 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 endo genously and after administration of 250 mg levodopa. Results Endogeno us concentrations of levodopa and 3-OMD increased dose-dependently (fr om 8 up to 52 mu gl(-1) and from 0.02 up to 0.50 mgl(-1), respectively , at doses of 200 mg) with ascending doses of benserazide whereas DOPA C 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 (AUG) of exogenously administe red levodopa increased from 1.2 in the control group to 5.9 mgl(-1) h at benserazide doses of 100-200 mg three times daily. Benserazide caus ed a dose-dependent increase in the AUC of 3-OMD from 7.4 to 106 mgl(- 1) h at doses of 200 mg. Formation of DOPAC was dose-dependently suppr essed, 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 comple tely inhibited.