Clinical Drug Investigation

, Volume 21, Issue 2, pp 147–156 | Cite as

Upper and Lower Limits in the Renal Clearance of Acetylmesalazine in Humans

Indications for Renal Acetylation of Mesalazine
  • Tom B. Vree
  • Erik Dammers
  • Peter S. Exler
  • Fritz Sörgel
  • Stig Bondesen
  • Robert A. A. Maes
Clinical Pharmacokinetic



To investigate upper and lower limits in the renal clearance of acetylmesalazine and mesalazine in humans.

Study Design

Renal clearance data were obtained from four randomised, crossover bioequivalence studies and one intravenous administration study in 200 healthy volunteers.


Study participants received tablets [gastroresistant single-dose 500mg (n = 24) and prolonged-release, single-dose 1000mg (n = 18); multiple-dose 1000mg three times daily for six days (n = 28)], suppositories [single-dose 500mg (n = 24)] and two intravenous administrations [100 and 250mg mesalazine (n = 6)]. In total 200 drug administrations were carried out, and plasma concentration-time curves and renal excretion rate-time profiles were obtained and analysed. Plasma and urine mesalazine and acetylmesalazine concentrations were determined according to validated methods using HPLC analysis with coulometric or mass spectrometric detection.


The metabolite acetylmesalazine was cleared renally via glomerular filtration and active tubular secretion resulting in renal clearance (CLr) values of 200 to 300 ml/min. The average renal clearance was 210 ml/min, 30% coefficient of variation (CV). Two phases in the upper limit of renal clearance can be distinguished, with renal clearance values of 430 and 340 ml/min, respectively. There was a lower limit of 120 ml/min. The CLr data of mesalazine demonstrated that after the saturable reabsorption process, mesalazine is filtered by the glomerulus, showing an upper limit of 100 ml/min and a lower limit of 1.5 ml/min. Variation in the renal clearance values of mesalazine and its metabolite acetylmesalazine are probably due to variations in cardiac output and hence renal blood flow. Combining the CLr data of mesalazine and acetylmesalazine showed that the saturable tubular reabsorption of mesalazine can also be explained as renal acetylation of mesalazine, resulting in the low CLr of mesalazine and the high CLr of acetylmesalazine.


The renal clearance of the metabolite acetylmesalazine proceeds via glomerular filtration plus active tubular secretion (200 to 300 ml/min). There is an upper (300 to 400 ml/min) and a lower (120 ml/min) limit of renal clearance values, which seem to be governed by physiological variations in the cardiac output. Moreover, saturable renal acetylation of mesalazine may contribute to the overall renal clearance of acetylmesalazine. This finding explains the dosage- and renal supply-dependent renal clearance values of both mesalazine and acetylmesalazine, but will have limited clinical implications as they can be classified as physiological variations. Implications may arise with renal impairment, with slowing down of both renal acetylation of mesalazine and renal excretion of the metabolite acetylmesalazine.


Renal Clearance Renal Blood Flow Mesalazine Tubular Reabsorption Pentasa 
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  1. 1.
    Ahnfelt-RHnne I, Nielsen OH, Christensen A, et al. Clinical evidence supporting the radical scavenger mechanism of 5- aminosalicylic acid. Gastroenterology 1990; 98: 1162–9Google 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 mesalazine 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 mesalazine 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: 73–7PubMedCrossRefGoogle 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.
    Vree TB, Dammers E, Exler PS, et al. Saturable active tubular reabsorption in the renal clearance of mesalazine in human volunteers. Clin Drug Invest 2000; 20: 35–42CrossRefGoogle Scholar
  11. 11.
    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
  12. 12.
    Vree TB, Dammers E, Exler PS, et al. Liver and gut acetylation of mesalazine in healthy volunteers. Int J Clin Pharmacol Ther 2000; 38: 514–22PubMedGoogle Scholar
  13. 13.
    Nielsen OH, Bondesen S. Kinetics of 5-aminosalicylic acid after jejunal installation in man. Br J Clin Pharmacol 1983; 16:738–40CrossRefGoogle Scholar
  14. 14.
    Jacobsen B A, 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
  15. 15.
    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; 52: 645–52PubMedCrossRefGoogle Scholar
  16. 16.
    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
  17. 17.
    Norlander B, Gotthard R, Ström M. Steady-state pharmacokinetics of enteric coated 5-aminosalicylic acid tablets in healthy volunteers and in patients with Chrohn’s disease or ulcerative colitis. Aliment Pharmacol Ther 1991; 5: 291–300PubMedCrossRefGoogle Scholar
  18. 18.
    Giochetti 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: 535–40CrossRefGoogle 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.
    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
  23. 23.
    Vree TB, Hekster YA, Hafkenscheid JCM, et al. The influence of urine flow on renal clearance of creatinine in patients with normal and impaired kidney function. Drug Intell Clin Pharm 1981; 15: 194–8PubMedGoogle Scholar
  24. 24.
    Vree TB, Hekster YA, Damsma JE, et al. Renal excretion of sulphamethoxazole and its metabolite N4-acetylsulpha-methoxazole in patients with impaired kidney function. Ther Drug Monit 1981; 3: 129–35PubMedCrossRefGoogle Scholar
  25. 25.
    VanDalen R, Vree TB, Hafkenscheid JCM, et al. Determination of plasma and renal clearance of cefuroxime and its pharmacokinetics in renal insufficiency. J Antimicrob Chemother 1979; 5: 281–92PubMedCrossRefGoogle Scholar
  26. 26.
    VanDalen R, Vree TB, Baars AM, et al. Dosage adjustments for ceftazidime in patients with impaired renal function. Eur J Clin Pharmacol 1986; 30: 597–605PubMedCrossRefGoogle Scholar
  27. 27.
    Vree TB, Beneken-Kolmer EWJ, Shimoda M, et al. Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfa-6-monomethoxine in humans. Drug Metab Dispos 1990; 18: 852–8PubMedGoogle Scholar
  28. 28.
    Schuster VL, Seldin DW. Renal clearance. In: Seidin DW, Giebisch G, editors. The Kidney, physiology and pathophysiology. 2nded, Volume 1, Raven Press, New York, 1992: 943–78Google Scholar
  29. 29.
    Sica DA, Schoolwerth AC. Renal handling of organic anions and cations and renal excretion of uric acid. In: Brenner BM, editor. The Kidney, 5th ed, volume 1, Philadelphia (PA): WB Saunders Company: 1996: 607–26Google Scholar
  30. 30.
    Lohr JW, Willsky GR, Acara MA. Renal drug metabolism. Pharmacol Rev 1998; 50: 107–42PubMedGoogle Scholar
  31. 31.
    Vree TB, Hekster YA, Anderson PG. Contribution of the human kidney to the metabolic clearance of drugs. Ann Pharmacother 1992; 26: 1421–8PubMedGoogle Scholar
  32. 32.
    Bonate PL, Reith K, Weir S. Drug interactions at the renal level. Implications for drug development. Clin Pharmacokinet 1998; 34: 375–404PubMedCrossRefGoogle Scholar
  33. 33.
    Verzijl JM, Kamphuis ThJ, Rensma PL, et al. Clearance of an oral delayed-release mesalazine preparation (Salofalk) by haemodialysis-pharmacokinetic profile of mesalazine related to effect of dialysis. Nephrol Dial Transplant 2000; 15: 736–8PubMedCrossRefGoogle Scholar
  34. 34.
    Visscher CA, deZeeuw D, deJong PE, et al. Drug-induced changes in renal hippurate clearance as a measure of renal blood flow. Kidney Int 1995; 48: 1617–23PubMedCrossRefGoogle Scholar
  35. 35.
    Pilkington LA, Binder R, deHaas JCM, et al. Intrarenal distribution of blood flow. Am J Physiol 1965; 208: 1107–13PubMedGoogle Scholar
  36. 36.
    Schlant RC, Sonnenblick EH. Normal physiology of the cardiovascular system. In: Schlant RC, Alexander RW, editors. The Heart, arteries and veins, 8th ed, Volume 1, McGraw-Hill, New York: 1994: 113–51Google Scholar
  37. 37.
    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
  38. 38.
    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
  39. 39.
    Calder IC, Funder CC, Gree CR, et al. Nephrotoxic lesions from 5-aminosalicylic acid. Br Med J 1972; 1: 152–4PubMedCrossRefGoogle Scholar
  40. 40.
    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
  41. 41.
    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 4377]. Proceedings Digestive Disease Week 1999 May 16–19, Orlando, Florida, USA, 1999, A-794-5Google Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  • Tom B. Vree
    • 1
  • Erik Dammers
    • 2
  • Peter S. Exler
    • 3
  • Fritz Sörgel
    • 4
  • Stig Bondesen
    • 5
  • Robert A. A. Maes
    • 6
  1. 1.Institute for AnaesthesiologyUniversity Medical Center 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.Frederiksberg HospitalFrederiksberg, CopenhagenDenmark
  6. 6.Department of Human ToxicologyUniversity of UtrechtUtrechtThe Netherlands

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