Saturable active tubular reabsorption in the renal clearance of mesalazinein human volunteers

Objective: To identify the reasons for the large variation in renal clearan ce 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 dif ferent formulations of prolonged release mesalazine (2 x 500mg tablets). Th e formulations had similar dissolution profiles in phosphate buffer pH 6.8. Plasma and urine mesalazine and acetylmesalazine concentrations were deter mined by validated methods involving high performance liquid chromatography analysis with mass spectrometric detection. Lower limits of quantification were 50 mu g/L and 50 mu g/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 mes alazine from both formulations and in the subsequent renal clearance of mes alazine. There was a clear distinction (p = 0.0009) in renal clearance betw een volunteers who showed slow mesalazine absorption with subsequent low cl earance [0.006 to 0.5 L/h (0.1 to 8 ml/min)] and those who showed mon exten sive 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 acetylme salazine is cleared renally via glomerular filtration and active tubular se cretion, 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 reabsorptio n 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 clearanc e of 0.5 L/h (8 ml/min). This finding explains the dosage-dependent renal c learance of mesalazine reported in the literature, but has no clear clinica l implications.