title: Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1.
abstract: OBJECTIVE
  The rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases (NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases (UGT) and glutathione S-transferases (GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine.
  
  
  METHODS
  Metabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release (IR) tablet (100 mg) and after repeated administration of modified release (MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain).
  
  
  RESULTS
  Flupirtine IR was rapidly but incompletely absorbed (∼ 72%). Repeated administration of flupirtine MR showed lower bioavailability (∼ 60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2.
  
  
  CONCLUSIONS
  Formation of mercapturic acid derivatives is a major elimination route for flupirtine in man. However, the theoretically toxic pathway is not influenced by the frequent polymorphisms of UGT1A1, NAT2 and GSTP1.
authors.affiliation: Department of Clinical Pharmacology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
authors.forename: Christiane
authors.initials: C
authors.lastname: Modess
authors.forename: Eberhard
authors.initials: E
authors.lastname: Scheuch
authors.forename: Karen
authors.initials: K
authors.lastname: Methling
authors.forename: Markus
authors.initials: M
authors.lastname: Keiser
authors.forename: Ali
authors.initials: A
authors.lastname: Nassif
authors.forename: Dieter
authors.initials: D
authors.lastname: Rosskopf
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bednarski
authors.forename: Jürgen
authors.initials: J
authors.lastname: Borlak
authors.forename: Bernd
authors.initials: B
authors.lastname: Terhaag
mesh_terms: D000328:Adult; D000818:Animals; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D055815:Young Adult; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000378:metabolism; D065767:Activation, Metabolic / Q000187:drug effects / Q000235:genetics; D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D001682:Biological Availability; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D064368:Healthy Volunteers; D007275:Injections, Intravenous; D061985:Madin Darby Canine Kidney Cells; D000089762:Multidrug Resistance-Associated Protein 2; D017288:Pain Threshold / Q000187:drug effects; D011110:Polymorphism, Genetic; D000099148:UGT1A1 Enzyme
chemical_list: D000111:Acetylcysteine; D000631:Aminopyridines; D000700:Analgesics; D001191:Arylamine N-Acetyltransferase; D003692:Delayed-Action Preparations; D014453:Glucuronosyltransferase; D051549:Glutathione S-Transferase pi; D000089762:Multidrug Resistance-Associated Protein 2; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human; C034161:flupirtine; C496556:GSTP1 protein, human; C478900:NAT2 protein, human
keywords: ABCB1; ABCC2; drug-induced liver disease; flupirtine; pharmacogenetics; quinone diimines