title: Mesalazine pharmacokinetics and NAT2 phenotype.
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.
  
  
  CONCLUSIONS
  NAT2 has no major role in human metabolism of mesalazine in vivo.
authors.affiliation: Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lück
authors.forename: Martina
authors.initials: M
authors.lastname: Kinzig
authors.forename: Alexander
authors.initials: A
authors.lastname: Jetter
authors.forename: Uwe
authors.initials: U
authors.lastname: Fuhr
authors.forename: Fritz
authors.initials: F
authors.lastname: Sörgel
mesh_terms: D000107:Acetylation; D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D002110:Caffeine / Q000652:urine; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D019804:Mesalamine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008954:Models, Biological; D010641:Phenotype; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002110:Caffeine; D019804:Mesalamine; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human