LACK OF BIOAVAILABILITY OF MEBEVERINE EVEN AFTER PRETREATMENT WITH PYRIDOSTIGMINE

Objective: After the oral administration of mebeverine to animal or hu man, measurable concen trations of the drug have never been found in t he plasma. The ex vivo hydrolysis of mebeverine can be blocked by este rase inhibitors. In the present study, human volunteers were pretreate d with pyridostigmine to attempt to improve the bioavailability of the parent drug. Methods: Following a single-blind, random design, 12 nor mal human volunteers received orally either placebo or 60 mg pyridosti gmine, followed 2 h later by 405 mg mebeverine. Blood samples were dra wn intermittently for 4 h and were spiked immediately with neostigmine in order to block ex vivo hydrolysis. Results: Even after pretreatmen t with pyridostigmine, the plasma samples failed to reveal detectable concentrations of mebeverine. Pyridostigmine pretreatment mediated a s ignificantly higher peak concentration of veratric acid, the acid moie ty resulting from hydrolysis of mebeverine. Conclusion: As mebeverine seemingly undergoes complete presystemic hydrolysis, it seems unlikely that the effects of the drug could be mediated centrally. Furthermore , as it is unlikely that sufficient mebeverine traverses the intestine to exert a local effect on the colon (i.e., the time-course of veratr ic acid plasma levels does not support such a conclusion), the therape utic effect of the drug, if any, has to be ascribed to an active metab olite. However, the hydrolysis products of mebeverine are not known to be pharmacologically active.