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(S)-N-(endo-8-Methyl-8-azabicyclo[3.2.1]oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyloxy)[carbonyl-14C]benzamide monohydrochloride (14C-E3620, 1 1), which was required for a study of the pharmacokinetic profile of E3620, is not only a potent antagonist of 5-HT3 receptors but also a potent agonist of 5-HT4 receptors. It was synthesized using (S)-5-chloro-4-(2,5-dimethylpyrrol-1-yl)-2-(1-methyl-2-butynyloxy)[carboxy-14C]benzoic acid (8) as the labelled starting material. © 1997 John Wiley & Sons, Ltd. The product was produced at high radiochemical purity with a specific activity of 2.02GBq / mmol.

Potency and duration of muscle relaxant activity of eperisone hydrochloride were examined after percutaneous administration in the intercollicular decerebrated rat rigidity model and compared to those of eperisone after intravenous injection. A continuous movement was loaded on the hindlimb of the rat model to maintain stable rigidity. The tonus of the hindlimb was recorded by EMG from the triceps surae and was quantified by using the public domain NIH Image program. Eperisone ointment administered percutaneously showed significant muscle relaxant activity at 8.4 cm2 (4.2 mg of eperisone)/rat. The effect was dose-dependent and lasted over 60 min. Intravenously injected eperisone showed significant activity at 1.25 mg/kg, but the decrease of tone was lost within 30 min after injection. Plasma eperisone levels were monitored in the same model, and they were well correlated to the dosage. These results suggest that percutaneously administered eperisone is absorbed efficiently and shows potent and long-lasting muscle relaxant activity.

Five male patients with extrahepatic cholelithasis and ten male patients with liver cirrhosis were administered simultaneously 4mg/kg trimethadione (TMO) and 500mg/man antipyrine (AP). Changes in phase I (AP and TMO) and phase II (AP) reactions of the model substrates in liver disease were examined. The patients with liver cirrhosis exhibited prolonged half-life (t1/2) and decreased metabolic clearance (CL) of AP when compared with cholelithasis patients, while no change was found in the apparent volume of distribution (Vd). The serum dimethadione (DMO)/TMO ratio at 4hr after oral administration of TMO was apparently decreased in the cirrhotic patients. The cirrhotic patients also exhibited significant decreases in urinary excretion and clearance for production of three major AP metabolites (4-hydroxyantipyrine, 3-hydroxymethyl-3-norantipyrine, and 3-hydroxymethylantipyrine), while no significant differences between the cirrhotic patients and cholelithasis patients were noted in percentages of either total or individual glucuronidation of these metabolites. These findings suggest that AP and TMO metabolisms (phase I) are severely impaired in cirrhotic patients, whereas glucuronidation of AP is unaffected (phase II).