title: Systemic levels of free 5-aminosalicylic acid depend on the nature of the 5-aminosalicyclic acid derivative and not on disease activity or extent in patients with inflammatory bowel disease.
abstract: BACKGROUND
  Several new derivatives of sulphasalazine that make use of its active moiety, 5-aminosalicylic acid (5-ASA), have been introduced for the treatment of inflammatory bowel disease (IBD). In rats short term intravenous administration of 5-ASA has been associated with nephrotoxicity. A number of cases of nephrotoxicity have been reported recently in IBD patients taking oral maintenance treatment with 5-ASA compounds.
  
  
  OBJECTIVE
  To study the urinary and serum levels of acetylated 5-ASA (Ac-5-ASA) and the unacetylated 5-ASA (5-ASA) in patients with IBD maintained on sulphasalazine, olsalazine and mesalazine (pH dependent release form). We also sought correlation between levels of 5-ASA, clinical disease activity and extent of disease.
  
  
  METHODS
  We studied 79 patients (male, n = 30; female, n = 49) with established IBD [ulcerative colitis (UC), n = 48; Crohn's disease (CD), n = 31], 72 maintained on 5-ASA compounds (sulphasalazine = 27; olsalazine = 28; mesalazine = 17) and 7 patients were receiving no medication. Urinary and serum analysis of 5-ASA was performed by high performance liquid chromatography (HPLC). Clinical disease activity was quantified using simple index of Harvey and Bradshaw.
  
  
  RESULTS
  Patients receiving mesalazine had significantly higher levels of serum free 5-ASA compared to those who were receiving olsalazine and sulphasalazine (mesalazine mean +/- SEM; range; 2.84 +/- 1.21 (0.00-16.00) vs olsalazine 0.45 +/- 0.18 (0.00-16.20); mumol/L; p < 0.04; sulphasalazine 0.37 +/- 0.25 (0.00-3.74); p < 0.03). Similarly levels of urinary free 5-ASA were significantly higher in patients maintained on mesalazine compared to those on olsalazine or sulphasalazine (mesalazine 219 +/- 80.43 (0.00-1050) vs olsalazine 33.3 +/- 17.23 (0.00-317) mumol/L; p < 0.01; and sulphasalazine 15 +/- 8.86 (0.00-192); p < 0.05). However, no significant difference was observed in the levels of urinary free 5-ASA between olsalazine and sulphasalazine. No significant difference was observed in the levels of free-5-ASA in UC patients with left sided disease and those with extensive disease. Furthermore, no significant difference was observed in the levels of serum and urinary 5-ASA in CD patients with ileo-colic disease and colonic disease. Urinary and serum free-5-ASA did not correlate with the clinical disease activity.
  
  
  CONCLUSIONS
  Systemic absorption of 5-ASA from sulphasalazine and olsalazine is relatively low. However, pH-dependent mesalazine formulations may release their contents rapidly in the small intestine and proximal colon resulting in higher plasma and urinary concentrations of free 5-ASA. The effects of free 5-ASA on renal function in the human require further evaluation.
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Republic of Ireland.
authors.forename: N
authors.initials: N
authors.lastname: Mahmud
authors.forename: D G
authors.initials: DG
authors.lastname: Weir
authors.forename: D
authors.initials: D
authors.lastname: Kelleher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000636:Aminosalicylic Acids / Q000009:adverse effects / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use / Q000652:urine*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005765:Gastrointestinal Agents / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D019804:Mesalamine / Q000378:metabolism / Q000627:therapeutic use; D008875:Middle Aged; D012044:Regression Analysis; D012460:Sulfasalazine / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005765:Gastrointestinal Agents; D012460:Sulfasalazine; D019804:Mesalamine; C032587:olsalazine