Clinical Drug Investigation

, Volume 20, Issue 1, pp 35–42 | Cite as

Saturable Active Tubular Reabsorption in the Renal Clearance of Mesalazine in Human Volunteers

  • Tom B. Vree
  • Erik Dammers
  • Peter S. Exler
  • Fritz Sörgel
  • Robert A. A. Maes
Clinical Pharmacokinetics


Objective: To identify the reasons for the large variation in renal clearance of mesalazine.

Design: Data were obtained from a randomised crossover bioequivalence study in 18 healthy volunteers.

Methods: Participants received a single 1000mg oral dose of each of two different formulations of prolonged release mesalazine (2 × 500mg tablets). The formulations had similar dissolution profiles in phosphate buffer pH 6.8. Plasma and urine mesalazine and acetylmesalazine concentrations were determined by validated methods involving high performance liquid chromatography analysis with mass spectrometric detection. Lower limits of quantification were 50 μg/L and 50 μg/L in plasma and 0.25 mg/L and 2 mg/L in urine, respectively.

Results: There was a large variability in the release and absorption of mesalazine from both formulations and in the subsequent renal clearance of mesalazine. There was a clear distinction (p = 0.0009) in renal clearance between volunteers who showed slow mesalazine absorption with subsequent low clearance [0.006 to 0.5 L/h (0.1 to 8 ml/min)] and those who showed more extensive absorption followed by higher renal clearance [0.5 to 6 L/h (8 to 100 ml/min)]. Active tubular reabsorption with a saturable maximum must be the explanation for this difference in renal clearance. The metabolite acetylmesalazine is cleared renally via glomerular filtration and active tubular secretion, resulting in a clearance of 12 to 18 L/h (200 to 300 ml/min).

Conclusion: The renal clearance of mesalazine proceeds via the processes of glomerular filtration and active tubular reabsorption. Tubular reabsorption shows saturation at an area under the plasma concentration-time curve of 4 mg/L·h with an excreted amount of 2mg, resulting in a threshold clearance of 0.5 L/h (8 ml/min). This finding explains the dosage-dependent renal clearance of mesalazine reported in the literature, but has no clear clinical implications.


Renal Clearance Mesalazine Select Reaction Monitoring Tubular Reabsorption Ammonium Acetate Buffer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Ahnfelt-Ronne I, Nielsen OH, Christensen A, et al. Clinical evidence supporting the radical scavenger mechanism of 5-aminosalicylic acid. Gastroenterology 1990; 98 (5 Pt 1): 1162–9PubMedGoogle Scholar
  2. 2.
    Prakash A, Markham A. Oral delayed-release mesalazine. A review of its use in ulcerative colitis and Crohn’s disease. Drugs 1999; 57: 383–408PubMedCrossRefGoogle Scholar
  3. 3.
    Martindale. Reynolds JEF, editor. The extra pharmacopoeia. 31st ed. Gastro-intestinal agents. Mesalazine. London: Pharmaceutical Press, 1996: 1227–8Google Scholar
  4. 4.
    Yu DK, Morrill B, Eichmeier LS, et al. Pharmacokinetics of 5-aminosalicylic acid from controlled-release capsules in man. Eur J Clin Pharmacol 1995; 48: 273–7PubMedCrossRefGoogle Scholar
  5. 5.
    Norlander B, Gotthard R, Ström M. Pharmacokinetics of a 5-aminosalicylic acid enteric-coated tablet in patients with Crohn’s disease or ulcerative colitis and in healthy volunteers. Aliment Pharmacol Ther 1990; 4: 497–505PubMedCrossRefGoogle Scholar
  6. 6.
    Bondesen S, Hegnhoj J, Larsen F, et al. Pharmacokinetics of 5-aminosalicylic acid in man following administration of intravenous bolus and per os slow-release formulation. Dig Dis Sci 1991; 36: 1735–40PubMedCrossRefGoogle Scholar
  7. 7.
    Brogden RN, Sorkin EM. Mesalazine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in chronic inflammatory bowel disease. Drugs 1989; 38: 500–23PubMedCrossRefGoogle Scholar
  8. 8.
    Järnerot G. Newer 5-aminosalicylic acid based drugs in chronic inflammatory bowel disease. Drugs 1989; 37: 73–6PubMedCrossRefGoogle Scholar
  9. 9.
    Meyers B, Evans DNW, Rhodes J, et al. Metabolism and urinary excretion of mesalazine in healthy volunteers given intravenously or released for absorption at different sites in the gastro-intestinal tract. Gut 1987; 28: 196–200CrossRefGoogle Scholar
  10. 10.
    Allgayer H, Sonnenbichler J, Kruis W, et al. Determination of the pK values of 5-aminosalicylic acid and N-acetylsalicylic acid and comparison of the pH dependent lipid-water partition coefficients of sulphasalazine and its metabolites. Arzneimittelforschung 1985; 35: 1457–9PubMedGoogle Scholar
  11. 11.
    Nielsen OH, Bondesen S. Kinetics of 5-aminosalicylic acid after jejunal installation in man. Br J Clin Pharmacol 1983; 16: 738–40CrossRefGoogle Scholar
  12. 12.
    Jacobsen BA, Abildgaard K, Rasmussen HH, et al. Availability of mesalazine from enemas and suppositories during steady state conditions. Scand J Gastroenterol 1991; 26: 374–8PubMedCrossRefGoogle Scholar
  13. 13.
    Vree TB, Dammers E, Exler PS, et al. Mono and biphasic plasma concentration-time curves of mesalazine from a 500 mg suppository in 24 healthy male volunteers controlled by the time of defecation before dosing. J Pharm Pharmacol 2000. In pressGoogle Scholar
  14. 14.
    Yu DK, Elvin AT, Morrill B, et al. Effect of food coadministration on 5-aminosalicylic acid oral suspension bioavailability. Clin Pharmacol Ther 1990; 48: 26–33PubMedCrossRefGoogle Scholar
  15. 15.
    Norlander B, Gotthard R, Ström M. Steady-state pharmacokinetics of enteric coated 5-aminosalicylic acid tablets in healthy volunteers and in patients with Crohn’s disease or ulcerative colitis. Aliment Pharmacol Ther 1991; 5: 291–300PubMedCrossRefGoogle Scholar
  16. 16.
    Gionchetti P, Campieri M, Belluzzi A, et al. Bioavailability of single and multiple doses of a new oral formulation of 5-ASA in patients with inflammatory bowel disease and healthy volunteers. Aliment Pharmacol Ther 1994; 8: 535–40PubMedCrossRefGoogle Scholar
  17. 17.
    Vree TB, Hekster YA, Baars AM, et al. Pharmacokinetics of sulphamethoxazole in man: effects of urinary pH and urine flow on metabolism and renal excretion of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole. Clin Pharmacokinet 1978; 3: 319–29PubMedCrossRefGoogle Scholar
  18. 18.
    Vree TB, van Ewijk-Beneken Kolmer EWJ, Verwey-Van Wissen CPWM, et al. Effect of urinary pH on the pharmacokinetics of salicylic acid, with its glycine and glucuronide conjugates in human. Int J Clin Pharmacol Ther 1994; 32: 550–8PubMedGoogle Scholar
  19. 19.
    Boom, SP, Wouterse AC, Vree TB, et al. Renal tubular excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine in the dog. J Pharm Pharmacol 1993; 45: 614–7PubMedCrossRefGoogle Scholar
  20. 20.
    Boom SP, Hoet S, Russel FG. Saturable urinary excretion kinetics of famotidine in the dog. J Pharm Pharmacol 1997; 49: 288–92PubMedCrossRefGoogle Scholar
  21. 21.
    Boom SP, Meyer I, Wouterse AC, et al. A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog. Biopharm Drug Dispos 1998; 19: 199–208PubMedCrossRefGoogle Scholar
  22. 22.
    Bondesen S, Rasmussen SN, Rask-Madsen J, et al. 5-Aminosalicylic acid in the treatment of inflammatory bowel disease. Acta Med Scand 1987; 221: 227–42PubMedCrossRefGoogle Scholar
  23. 23.
    Diener U, Tuczek HV, Fischer C, et al. Renal function was not impaired by treatment with 5-aminosalicylic acid in rats and man. Naunyn Schmiedebergs Arch Pharmacol 1984; 326: 278–82PubMedCrossRefGoogle Scholar
  24. 24.
    Calder IC, Funder CC, Gree CR, et al. Nephrotoxic lesions from 5-aminosalicylic acid. BMJ 1972; 1: 152–4PubMedCrossRefGoogle Scholar
  25. 25.
    Noble E, Janssen L, Dierickx PJ. Comparative cytotoxicity of 5-aminosalicylic acid (mesalazine) and related compounds in different cell lines. Cell Biol Toxicol 1997; 13: 445–51PubMedCrossRefGoogle Scholar
  26. 26.
    Fraser JS, Smith D, Lamb E, et al. Prospective study of the effect of 5-aminosalicylic acid (mesalazine) on renal function in inflammatory bowel disease [abstract no. 4377]. Proceedings Digestive Disease Week. 1999 May 16–19; Orlando, Florida, USA; 1999: A-794-5Google Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Tom B. Vree
    • 1
  • Erik Dammers
    • 2
  • Peter S. Exler
    • 3
  • Fritz Sörgel
    • 4
  • Robert A. A. Maes
    • 5
  1. 1.Institute for AnaesthesiologyAcademic Hospital Nijmegen Sint RadboudNijmegenThe Netherlands
  2. 2.DADA ConsultancyNijmegenThe Netherlands
  3. 3.Disphar InternationalHengelo (Gld)The Netherlands
  4. 4.Institute for Biomedical and Pharmaceutical ResearchNürnberg-HeroldsbergGermany
  5. 5.Department of Human ToxicologyUniversity of UtrechtUtrechtThe Netherlands

Personalised recommendations