Liver and gut mucosa acetylation of mesalazine in healthy volunteers

Aim: The aim of this investigation was to identify which part of a dose mes alazine is acetylated by enzymes in the gut wall during the absorption proc ess, and which part by the liver enzymes after absorption. Method: This stu dy was based on data from four bioequivalence studies of different formulat ions of tablets (gastro-resistant single dose 500 mg (n = 24) and prolonged -release tablets (single dose 1000 mg, n = 18; multiple dose 1000 mg t.i.d, six days n = 28), suppositories (single 500 mg dose, n = 24) and a study w ith two i.v. administrations of 100 and 250 mg mesalazine (n = 6). In total , 200 administrations were carried out and plasma concentration-time curves obtained and analyzed. There was a large variability in the absorption of mesalazine for all formulations. The plasma concentration-time curves of pa rent drug and metabolite acetylmesalazine run nearly parallel, independent of the formulation and the dose. Plasma and urine mesalazine and acetylmesa lazine concentrations were determined according to validated methods using HPLC analysis with coulometric or mass-spectrometric detection. Results: As a result of the large variations in release and absorption of mesalazine i n the pharmaceutical formulations and administrations, it was possible to d emonstrate that acetylation occurs in the gut wall and in the liver. By com paring oral and rectal data to intravenous data, it was possible to indicat e where land to what extent) acetylation occurs in the gut wall, in the liv er, or both. Rectal administration of a mesalazine suppository and intraven ous administration results in hepatic acetylation. Oral administrations of mesalazine results in both gut wall and hepatic acetylation. Acetylation by the gut wall amounts to 30% of the dose for gastro-resistant tablets and t o 40% of the dose for prolonged-release tablets.