title: Decreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1alpha-deficient mice: a mechanism for hypersensitivity to sulfonylurea therapy in patients with maturity-onset diabetes of the young, type 3 (MODY3).
abstract: Diabetes in subjects with hepatocyte nuclear factor (HNF)-1alpha gene mutations (maturity-onset diabetes of the young [MODY]-3) is characterized by impaired insulin secretion. Surprisingly, MODY3 patients exhibit hypersensitivity to the hypoglycemic actions of sulfonylurea therapy. To study the pharmacogenetic mechanism(s), we have investigated glibenclamide-induced insulin secretion, glibenclamide clearance from the blood, and glibenclamide metabolism in wild-type and Hnf-1alpha-deficient mice. We show that despite a profound defect in glucose-stimulated insulin secretion, diabetic Hnf-1alpha(-/-) mice have a robust glibenclamide-induced insulin secretory response. We demonstrate that the half-life (t(1/2)) of glibenclamide in the blood is increased in Hnf-1alpha(-/-) mice compared with wild-type littermates (3.9 +/- 1.3 vs. 1.5 +/- 1.8 min, P <or= 0.05). The clearance of glibenclamide from the blood during the first hours after intravenous administration was reduced approximately fourfold in Hnf-1alpha(-/-) mice compared with Hnf-1alpha(+/+) littermates. Glibenclamide uptake into hepatocytes was dramatically decreased in vivo and in vitro. To study the metabolism of glibenclamide in Hnf-1alpha(-/-) animals, we analyzed liver extracts from [(3)H]glibenclamide-injected animals by reverse-phase chromatography. We found that the ratio of the concentrations of glibenclamide and its metabolites was moderately increased in livers of Hnf-1alpha(-/-) mice, suggesting that hepatic glibenclamide metabolism was not impaired in animals with Hnf-1alpha deficiency. Our data demonstrate that high serum glibenclamide concentrations and an increased t(1/2) of glibenclamide in the blood of Hnf-1alpha(-/-) mice are caused by a defect in hepatic uptake of glibenclamide. This suggests that hypersensitivity to sulfonylureas in MODY3 patients may be due to impaired hepatic clearance and elevated plasma concentrations of the drug.
authors.affiliation: Laboratory of Metabolic Diseases, the Rockefeller University, New York, New York 10021, USA.
authors.forename: Pascal
authors.initials: P
authors.lastname: Boileau
authors.forename: Christian
authors.initials: C
authors.lastname: Wolfrum
authors.forename: David Q
authors.initials: DQ
authors.lastname: Shih
authors.forename: Tien-An
authors.initials: TA
authors.lastname: Yang
authors.forename: Allan W
authors.initials: AW
authors.lastname: Wolkoff
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D004342:Drug Hypersensitivity / Q000209:etiology*; D005905:Glyburide / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D022781:Hepatocytes / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009687:Nuclear Proteins; D013453:Sulfonylurea Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D009687:Nuclear Proteins; D013453:Sulfonylurea Compounds; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D005905:Glyburide