THE EFFECTS OF COADMINISTRATION OF BENZHEXOL ON THE PERIPHERAL PHARMACOKINETICS OF ORAL LEVODOPA IN YOUNG VOLUNTEERS

1 The effects of benzhexol on the absorption and pharmacokinetics of a n oral dose of levodopa have been studied in 10 young healthy voluntee rs. Subjects were given a suspension of levodopa (250 mg) 90 min after either benzhexol (5 mg) or placebo in a randomized cross over design with doses separated by at least 1 week; on each occasion carbidopa wa s given Ih before and 5 h after the dose of levodopa. Soluble paraceta mol and radiolabelled DTPA were given with the levodopa as markers of gastric emptying. 2 Most subjects showed two peaks in the levodopa pla sma concentration-time curve on the placebo day, with the second minor peak occurring 1-2 h after the dose. After benzhexol administration a ll subjects showed two or more peak levodopa concentrations in plasma. Benzhexol administration caused a significant decrease in the maximum concentration (43%; P<0.05) of the initial peak and an increase (22%; P<0.1) in the maximum concentration of the second peak. This change i n absorption profile caused by benzhexol significantly altered the rat ios of the second peak compared with the initial peak for both the max imum concentrations (P<0.02) and for the AUC values (P<0.05). Benzhexo l administration did not affect the total AUC of levodopa (7.30+/-1.09 vs 7.19+/-1.26 mu g ml(-1) h; means+/-s.d.). 3 The plasma concentrati on-time curves for paracetamol showed similar profiles to those for le vodopa and the ratios of the peak concentrations and AUC values for th e second peak compared with the initial peak were increased significan tly by benzhexol administration (P<0.05). The total AUC of paracetamol was not affected by benzhexol administration (39.4+/-8.2 vs 40.0+/-8. 9 mu g ml(-1) h; mean+/-s.d.) 4 Benzhexol altered the gastric emptying profile, shown by gamma-scintigraphy, with a reduced extent of initia l emptying prior to the establishment of the plateau which is characte ristic of levodopa administration in the fasting state. In consequence the ratio of the second to the initial phase of emptying was signific antly higher (P<0.01) following benzhexol treatment. 5 Benzhexol reduc es the initial phase of gastric emptying after a dose of levodopa so t hat there is a decrease in the initial peak and a greater proportion o f the dose is absorbed subsequently following the second phase of gast ric emptying which occurs approximately 1 h later. Theoretically, this altered concentration-time profile could be an advantage for some pat ients with Parkinson's disease.