5-Aminosalicylic acid containing drugs. Delivery, fate, and possible clinical implications in man.

Since the beginning of the 1940s salazosulfapyridine (SASP) has been used in the treatment of chronic inflammatory bowel disease (CIBD). Almost 40 years later 5-aminosalicylic acid (5-ASA), which is split off by azo-reducing enzymes in the colon, was identified as the therapeutically active moiety of SASP. Thus different 5-ASA containing drugs were produced from which 5-ASA is released in the small and large intestine in a pH-dependent manner. Since there is a firm clinical indication that the 5-ASA concentration in the gut lumen is decisive for the therapeutic effect, a method was developed to evaluate the 5-ASA concentration at different levels in the intestine. The method was subsequently used to clarify factors of importance for the release of 5-ASA from the preparations. Ileostomy patients and healthy volunteers were investigated during continuous treatment with the three 5-ASA containing drugs with pH-dependent 5-ASA release: Asacol, Mesasal (Salofalk, Claversal), and Pentasa. The study confirmed release of 5-ASA in the small intestine from all preparations, but at different levels and speeds. Despite similar peroral dosage, very different 5-ASA concentration profiles were found in the ileostomy effluents, reflecting not only the difference in the release pattern of the preparations, but also the influence of the gastric residence time for larger sized tablets. The 5-ASA concentrations increased in the faeces of healthy volunteers. Furthermore the systemically absorbed fraction of 5-ASA was larger than previously found after SASP. The 5-ASA release from the preparation with the most proximal release, Pentasa, was less influenced by acceleration of the intestinal transit time than previously demonstrated after SASP in a similar study design. A comparative study of children given SASP and Pentasa showed similar results as in adults: a tendency for smaller 5-ASA concentration at rectal level after Pentasa than after SASP, and also larger systemic absorption. Despite higher 5-ASA dose per kg body weight, lower 5-ASA concentrations were seen in the faeces after both preparations, compared with adults. A peroral dose increase of Pentasa in healthy adults resulted in higher intraluminal 5-ASA concentration in the gut lumen, but also in saturation of the local and probably also systemic acetylation capacity, demonstrated by higher plasma concentrations and larger urinary excretion of 5-ASA. Similar faecal water concentrations were found after Pentasa 4 g and the azo-bond preparation with colonic 5-ASA release, Dipentum (olsalazine) 2 g, confirming the substantial 5-ASA release from Pentasa in the small intestine. Investigation of pregnant patients treated with different 5-ASA containing drugs showed a similar pattern to SASP treatment: small amounts of 5-ASA cross the placenta, whereas the concentration of the metabolite Ac-5-ASA is similar in the maternal and fetal circulations. Only minute amounts of 5-ASA were found in milk from nursing mothers, while the concentrations of Ac-5-ASA were considerably higher. The decrease in the semen quality during SASP treatment was improved by changing to a controlled-release 5-ASA drug. The concentrations of 5-ASA in seminal plasma were similar during the two treatment periods, but higher of its metabolite Ac-5-ASA during treatment with the controlled-release preparation. That indicates that the toxic effect after SASP is not caused by the 5-ASA or Ac-5-ASA moiety. All the preparations have proved effective in the treatment of ulcerative colitis, but data concerning the 5-ASA treatment of Crohn's disease are conflicting. Knowledge of the demonstrated differences in the release profiles of the 5-ASA containing drugs is therefore important when designing future clinical trials.