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

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.