title: Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a(-/-) Model.
abstract: OBJECTIVE
  Sulfonylurea derivatives are widely used for clinical treatment of human subjects with Maturity Onset Diabetes of the Young (MODY) caused by mutations in HNF-1α or HNF-4α despite the mechanism leading to their hypersensitivity is incompletely understood. In Hnf1a(-/-) mice, serum concentrations and half-life of sulfonylurea derivatives are strongly increased. We thus hypothesized that reduced sulfonylurea derivatives clearance stands behind their therapeutic potential in human HNF1A/HNF4A MODY subjects.
  
  
  METHODS
  Single doses of 3 mg glipizide and 5 mg glibenclamide/glyburide were administered sequentially to seven HNF1A/HNF4A MODY subjects and six control individuals matched for their age, BMI and CYP2C9 genotype. Pharmacokinetic (plasma concentration levels, Cmax, tmax, t1/2, AUC) and pharmacodynamic parameters (glycemia, C-peptide and insulin plasma levels) were followed for 24 hours after drug administration.
  
  
  RESULTS
  We provide the first evidence on the pharmacokinetics and pharmacodynamics of sulfonylurea derivatives in human MODY subjects. The half-life of glipizide did not change, and reached 3.8±0.7 and 3.7±1.8 h in the MODY and control subjects, respectively. The half-life of glibenclamide was increased only in some MODY subjects (t1/2 9.5±6.7 and 5.0±1.4 h, respectively). Importantly, the intra- individual responses of MODY (but control) subjects to glipizide and glibenclamide treatment were highly correlated. With regards to pharmacodynamics, we observed a differential response of control but not MODY subjects to the doses of glipizide and glibenclamide applied.
  
  
  CONCLUSIONS
  We rejected the hypothesis that all human MODY-associated mutations in HNF1A / HNF4A induce changes in the pharmacokinetics of sulfonylureas in humans analogically to the Hnf1a(-/-) mouse model.
authors.forename: Jana
authors.initials: J
authors.lastname: Urbanova
authors.forename: Michal
authors.initials: M
authors.lastname: Andel
authors.forename: Jana
authors.initials: J
authors.lastname: Potockova
authors.forename: Josef
authors.initials: J
authors.lastname: Klima
authors.forename: Jan
authors.initials: J
authors.lastname: Macek
authors.forename: Pavel
authors.initials: P
authors.lastname: Ptacek
authors.forename: Vaclav
authors.initials: V
authors.lastname: Mat'oska
authors.forename: Tereza
authors.initials: T
authors.lastname: Kumstyrova
authors.affiliation: Center for Research in Diabetes, Metabolism and Nutrition, 2nd Department of Internal Medicine, Third Faculty of Medicine, Charles University in Prague, Ruska 87, CZ-100 00 Prague, Czech Republic. petr.heneberg@lf3.cuni.cz.
authors.forename: Petr
authors.initials: P
authors.lastname: Heneberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018095:Germ-Line Mutation; D006207:Half-Life; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D013453:Sulfonylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D013453:Sulfonylurea Compounds