Objectives: Sulfonylurea derivatives are widely used for clinical treatment of human subjects with Maturity
Onset Diabetes of the Young (MODY) caused by mutations in HNF-1 or HNF-4 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.
Design and 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
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.