The effects of co‐administration of benzhexol on the peripheral pharmacokinetics of oral levodopa in young volunteers

Abstract

1 The effects of benzhexol on the absorption and pharmacokinetics of an oral dose of levodopa have been studied in 10 young healthy volunteers. 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 was given 1 h before and 5 h after the dose of levodopa. Soluble paracetamol and radiolabelled DTPA were given with the levodopa as markers of gastric emptying. 2 Most subjects showed two peaks in the levodopa plasma concentration-time curve on the placebo day, with the second minor peak occurring 1-2 h after the dose. After benzhexol administration all 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 in absorption profile caused by benzhexol significantly altered the ratios of the second peak compared with the initial peak for both the maximum concentrations (P<0.02) and for the AUC values (P<0.05). Benzhexol administration did not affect the total AUC of levodopa (7.30±1.09 vs 7.19±1.26 mg ml−1 h; means±s.d.). 3 The plasma concentration-time curves for paracetamol showed similar profiles to those for levodopa and the ratios of the peak concentrations and AUC values for the second peak compared with the initial peak were increased significantly 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 mg ml−1 h; mean±s.d.) 4 Benzhexol altered the gastric emptying profile, shown by c-scintigraphy, with a reduced extent of initial emptying prior to the establishment of the plateau which is characteristic of levodopa administration in the fasting state. In consequence the ratio of the second to the initial phase of emptying was significantly higher (P<0.01) following benzhexol treatment. 5 Benzhexol reduces the initial phase of gastric emptying after a dose of levodopa so that there is a decrease in the initial peak and a greater proportion of the dose is absorbed subsequently following the second phase of gastric emptying which occurs approximately 1 h later. Theoretically, this altered concentration-time profile could be an advantage for some patients with Parkinson's disease.

Guide for judicious use of the paracetamol absorption technique in a study of gastric emptying rate of liquids

“…Some investigators have found a significant correlation between the parameters for the rate of paracetamol absorption and scintigraphically measured gastric half-emptying time, the "gold standard" for GER measurement, 9,[12][13][14][15] but others have failed to find such correlation. 16,17 Based on the absence of "significant" correlation, the validity of the paracetamol method has been challenged.…”

“…18 On the other hand, in research favoring the paracetamol method, the range of half-emptying time was expanded by enrolling patients with a possible disorder in GER 13 or by pharmacological interventions. 15 As a result, a significant correlation would be disclosed. Based on these findings, we believe that real correlation exists between the rate of paracetamol absorption and the scintigraphy-based measurement of GER, although the strength of the cor-…”

WAGNER‐NELSON METHOD FOR ANALYSING THE ATYPICAL DOUBLE‐PEAKED [13CO2] EXCRETION CURVE IN THE [13C]‐OCTANOATE GASTRIC EMPTYING BREATH TEST IN HUMANS

“…Serial studies have documented definite relationships between scintigraphically assessed gastric emptying profiles and double‐peak patterns in the time versus plasma concentration curves of oral paracetamol, which is the gastric emptying marker, as follows: 7–10 (i) separation of a gastric emptying process by a period of very slow or quiescent emptying (the plateau) generates the double‐peak; (ii) the magnitude of the fraction emptied by the time at the beginning of the plateau is related directly to the relative size of the two peaks, with the larger the initial fraction emptied, the higher the initial peak concentration; (iii) the plateau phase emerges immediately after the initial peak is achieved; and (iv) the time at the end of the plateau period agrees with the time at the trough concentration. These scenarios have been reproduced very precisely by the Wagner‐Nelson method applied to OBT as shown above.…”

“…The [ 13 CO 2 ] excretion curve occasionally exhibits an atypical double‐peaking behaviour, which results in poor curve fitting 6 . Previous investigations on gastric emptying and paracetamol have suggested that plasma paracetamol concentration–time profiles manifest the double‐peak phenomenon when two emptying phases are separated by an interval of a quiescent (plateau) emptying phase 7–10 . Thus, it is reasonable to consider that the presence of the plateau emptying phase is also responsible for the occurrence of dual peaking [ 13 CO 2 ] excretion.…”

Μελέτη Της Κινητικότητας Του Στομάχου Σε Διαβητικούς Ασθενείς

“…• Για την επίδραση διαφόρων φαρµάκων (φάρµακα χρησιµοποιούµενα κατά της ηµικρανίας 211,212 , χηµειοθεραπευτικά 213,214 , θεοφυλλίνη 215 , λεβοντόπα 216,217 , µη στεροειδή αντιφλεγµονώδη 218 , β-αγωνιστές 219 , σκευάσµατα ασβεστίου 220 και ιχνοστοιχεία 221 , ατροπίνη 222 , ασπιρίνη 223 , ντοπαµίνη 224 , αναστολείς διαύλων ασβεστίου 225 και διουρητικά 226 ) στην ΓΚ και την µελέτη της φαρµακοκινητικής τους.…”