Upper and lower limits in the renal clearance of acetylmesalazine in humans - Indications for renal acetylation of mesalazine

Objective: 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, cros sover bioequivalence studies and one intravenous administration study in 20 0 healthy volunteers. Methods: Study participants received tablets [gastroresistant single-dose 5 00mg (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 me salazine (n = 6)]. In total 200 drug administrations were carried out, and plasma concentration-time curves and renal excretion rate-time profiles wer e obtained and analysed. Plasma and urine mesalazine and acetylmesalazine c oncentrations were determined according to validated methods using HPLC ana lysis with coulometric or mass spectrometric detection. Results: 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, 3 0% coefficient of variation (CV). Two phases in the upper limit of renal cl earance 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, mesa lazine 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 variati ons in cardiac output and hence renal blood flow. Combining the CLR data of mesalazine and acetylmesalazine showed that the saturable tubular reabsorp tion of mesalazine can also be explained as renal acetylation of mesalazine , resulting in the low CLR of mesalazine and the high CLR of acetylmesalazi ne. Conclusion: 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 variatio ns in the cardiac output. Moreover, saturable renal acetylation of mesalazi ne may contribute to the overall renal clearance of acetylmesalazine. This finding explains the dosage- and and renal supply-dependent renal clearance values of both mesalazine and acetylmesalazine, but will have limited clin ical implications as they can be classified as physiological variations. Im plications may arise with renal impairment, with slowing down of both renal acetylation of mesalazine and renal excretion sf the metabolite acetylmesa lazine.