Comparative analysis of the in vitro prosecretory effects of balsalazide, sulfasalazine, olsalazine, and mesalamine in rabbit distal ileum.
BACKGROUND
The aminosalicylates remain foundation therapy for mild-to-moderate ulcerative colitis. Pro-drug 5-aminosalicylic acid (5-ASA; mesalamine) formulations have been developed to prevent 5-ASA from the proximal absorption and release of mesalamine, to decrease inflammation, and to improve colonic absorption. Clinically, pro-drugs such as olsalazine have been associated with dose-dependent diarrhea, which was likely secondary to ileal secretion induced by the azo linkages, in 17% of patients. The present study tested the hypothesis that the use of all compounds with azo linkages leads to increased secretion.


METHODS
Intestinal tissue was randomly assigned to serve as controls or to receive brush border addition of equimolar concentrations of the compounds, and the change in short-circuit current was measured.


RESULTS
Mesalamine did not induce secretion at any dose. Mean equivalent doses (0.1 to 10 mM) of balsalazide (range, 6.3 +/- 1.5 to 16.7 +/- 1.3 microA/cm2), olsalazine (range, 2.0 +/- 1.0 to 7.0 +/- 2.1 microA/cm2), and sulfasalazine (3.2 +/- 1.1 to 6.2 +/- 1.5 microA/cm2) significantly stimulated (P < 0.001) secretion. The values for the effective dose that is half the maximal dose for secretion induced by sulfasalazine, olsalazine, and balsalazide were 0.4, 0.7, and 0.9 mM, respectively.


CONCLUSIONS
This study is the first to demonstrate that the use of pro-drugs with azo bonds leads to increased ileal secretion at equimolar concentrations of 5-ASA. Physicians should use caution when providing higher doses of the pro-drug forms of 5-ASA to their patients, as this could lead to increased diarrhea.
Kles
Keri A
KA
Martin Boyer Laboratories, The University of Chicago IBD Research Center, Chicago, IL, USA.
Vavricka
Stephan R
SR
Turner
Jerrold R
JR
Musch
Mark W
MW
Hanauer
Stephen B
SB
Chang
Eugene B
EB
D000636:Aminosalicylic Acids / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000188:drug therapy; D003967:Diarrhea / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism*; D019804:Mesalamine / Q000494:pharmacology*; D010659:Phenylhydrazines; D011355:Prodrugs; D011817:Rabbits; D011897:Random Allocation; D012460:Sulfasalazine / Q000494:pharmacology*; D046509:Tissue Culture Techniques
D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D005765:Gastrointestinal Agents; D010659:Phenylhydrazines; D011355:Prodrugs; D012460:Sulfasalazine; D019804:Mesalamine; C038637:balsalazide; C032587:olsalazine