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.

The enantioselective protein binding of mephobarbital (MPB) was investigated in human plasma and human serum albumin solutions by equilibrium dialysis. A small but statistically significant difference was observed in the in vitro plasma protein binding of the enantiomers; (S)-MPB was approximately 59% bound and (R)-MPB approximately 67% bound. The binding to albumin [(S)-MPB: approximately 29% bound, and (R)-MPB: approximately 41% bound] was less than to plasma proteins but showed somewhat greater enantioselectivity, suggesting that albumin binding is a major source of the enantioselectivity in plasma. The effects of MPB concentration, of varying enantiomeric concentration ratio, and of phenobarbital on the enantioselective binding of MPB were studied. The effect of age was also investigated by measuring the binding in plasma from 8 young (18-25 yr) and 8 elderly (greater than 60 yr) male subjects who took single doses of MPB. The results were in close agreement with the in vitro binding data, and the binding of both enantiomers was marginally but significantly lower in the young compared with the elderly subjects. These differences in binding were consistent with previously observed pharmacokinetic differences between the two subject groups.

Racemic ethotoin (1000 mg) was administered orally as a single dose to six healthy adult volunteers. Blood samples were collected at appropriate times for 120 h following the dose. Ethotoin was quantified enantio-selectively in plasma using a novel chiral column HPLC procedure. One of the enantiomers of the chiral metabolite, 5-phenylhydantoin, was also quantified in the HPLC method. The Cmax and AUC0-infinity values for (+)-(S)-ethotoin were significantly greater than those for (-)-(R)-ethotoin (ratio of mean AUC0-infinity values 0.88), but the elimination half-lives of the isomers were virtually identical [12.35 +/- 5.15 h for (-)-(R)-ethotoin; 12.28 +/- 5.34 h for (+)-(S)-ethotoin]. Parameters derived from AUC0-infinity (Cl0/F and V(area)/F) also differed slightly between the isomers. The data were interpreted as indicating a small difference in the absorption of the two isomers; it seemed unlikely, in terms of the identical elimination rates, that their metabolic profiles would differ greatly. The 5-phenylhydantoin was eliminated with a significantly longer half-life (18.69 +/- 6.11 h) than that of ethotoin. Enantioselectivity in the pharmacokinetics of ethotoin is therefore a minor issue.

The plasma pharmacokinetics of levodopa were studied in eight healthy young subjects following an i.v. infusion of 50 mg over 5 min. Subjects were studied on two occasions in random order following treatment with carbidopa; on one occasion they were pretreated with selegiline (four doses of 10 mg over the preceding 3 days) and on the other with a placebo. The mean plasma concentration-time curves on each occasion were essentially superimposable and there were no significant differences in any calculated pharmacokinetic parameter. Selegiline does not significantly alter the distribution or elimination of levodopa from plasma.