FACILE HYDROLYSIS OF MEBEVERINE INVITRO AND INVIVO - NEGLIGIBLE CIRCULATING CONCENTRATIONS OF THE DRUG AFTER ORAL-ADMINISTRATION

The HPLC methods for the determination of plasma concentrations of the antispasmodic agent mebeverine (0.01-10-mu-g/mL) and its hydrolysis product veratric acid (0.1-50-mu-g/mL) are presented. Mebeverine was demonstrated to hydrolyze readily in fresh unbuffered human and rat plasma samples ex vivo. Hydrolysis in human plasma was completely inhibited in the presence of the esterase inhibitor physostigmine sulfate, at a concentration of 130-mu-g/mL. However, the inhibitor was only partially effective in blocking mebeverine hydrolysis in rat plasma. After oral administration of mebeverine . HCl (270 mg) to fasted human volunteers, measurable concentrations of the drug were not found in plasma. By contrast, the metabolite veratric acid achieved considerable concentrations (mean peak plasma concentration of 13.5-mu-g/mL at 40-80 min). After iv administration of mebeverine . HCl (2 mg) to rats, the drug was rapidly eliminated from plasma (mean half-life of 29 min) with simultaneous appearance of veratric acid (mean peak plasma concentration of 1.80-mu-g/mL at 15-30 min). However, after oral administration of the same dose, only traces of mebeverine were found in plasma, with the exception of one rat. Veratric acid again achieved considerable concentrations (mean peak plasma concentration of 0.90-mu-g/mL at 15 min-4 h). The results show that mebeverine undergoes rapid and extensive first-pass metabolism involving hydrolysis of the ester function, and that negligible circulating concentrations of the parent drug are found in humans.