Abstract

BACKGROUND: Mesalazine undergoes extensive metabolism by N-acetylation. While there is some evidence for an involvement of N-acetyltransferase (NAT) type 1, a potential role of NAT type 2 (NAT2) in vivo has not been tested. METHODS: In two studies in healthy young Caucasians, NAT2 phenotyping was carried out using a caffeine metabolic ratio in urine 4-6 h postdose. In study A, 1,000 mg mesalazine doses were given thrice daily for 5 days, and urine and blood samples were drawn during the last dosing interval. In study B, a 1,000 mg single dose was given, and samples were taken for 48 h postdose. Pharmacokinetics of mesalazine and N-acetylmesalazine (LC-MS/MS) were calculated by noncompartmental methods. RESULTS: NAT2 phenotype could be allocated unequivocally in 21 slow and 5 rapid acetylators in study A, and in 9 slow and 8 rapid acetylators in study B. Geometric mean (CV%) values in study A for slow [rapid] acetylators were as follows: mesalazine AUC 11.1 microg/mL.h (51%) [12.0 microg/mL.h (52%)], N-acetylmesalazine AUC 27.7 microg/mL.h (32%) [30.5 microg/mL.h (27%)], mesalazine Ae 8.53% (89%) [9.03% (52%)], N-acetylmesalazine Ae 31.4% (46%) [32.2 (41%)]. Values in study B were as follows: mesalazine AUC 3.45 microg/mL.h (113%) [2.36 microg/mL.h (87%)], N-acetylmesalazine AUC 21.3 microg/mL.h (29%) [18.0 microg/mL.h (39%)], mesalazine Ae 0.2% (256%) [0.1% (359%)], N-acetylmesalazine Ae 30.9% (44%) [18.1% (84%)]. Higher AUC and Ae values for mesalazine in steady state study indicate saturation of mesalazine metabolism. Statistics provided no evidence for a true difference in mesalazine pharmacokinetics between slow and rapid acetylators, and no significant correlation between NAT2 activity and any mesalazine pharmacokinetic parameter was found. CONCLUSION: NAT2 has no major role in human metabolism of mesalazine in vivo.