Mesalazine pharmacokinetics and NAT2 phenotype

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 μg/mL·h (51%) 12.0 μg/mL·h (52%)], N-acetylmesalazine AUC 27.7 μg/mL·h (32%) 30.5 μg/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 μg/mL·h (113%) 2.36 μg/mL·h (87%)], N-acetylmesalazine AUC 21.3 μg/mL·h (29%) 18.0 μg/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.