Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a-/- Model

Author(s): Jana Urbanova, Michal Andel, Jana Potockova, Josef Klima, Jan Macek, Pavel Ptacek, Vaclav  Mat’oska, Tereza Kumstyrova, Petr Heneberg.

Journal Name: Current Pharmaceutical Design

Volume 21 , Issue 39 , 2015

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Abstract:

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 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.

Keywords: Diabeta, glibenclamide, glipizide, glucotrol, glyburide, glynase, liver oxidation of xenobiotics, micronase, MODY diabetes, second generation sulfonylurea.

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Article Details

VOLUME: 21
ISSUE: 39
Year: 2015
Page: [5736 - 5748]
Pages: 13
DOI: 10.2174/1381612821666151008124036
Price: $58

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