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-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. 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.
- MeSH
- diabetes mellitus 2. typu farmakoterapie genetika metabolismus MeSH
- dospělí MeSH
- hepatocytární jaderný faktor 1-alfa genetika MeSH
- hepatocytární jaderný faktor 4 genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- modely nemocí na zvířatech * MeSH
- myši knockoutované MeSH
- myši MeSH
- poločas MeSH
- studie případů a kontrol MeSH
- sulfonylmočovinové sloučeniny škodlivé účinky farmakokinetika MeSH
- zárodečné mutace MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
A liquid chromatography-electrospray tandem mass spectrometry method was developed and validated to quantitate celecoxib in human plasma. The assay was based on protein precipitation with methanol and liquid chromatography on a C₁₈ column (55 mm × 2 mm, 3 μm), the mobile phase consisted of methanol-10 mM ammonium acetate (75:25, v/v). Quantification was performed by mass spectrometry in the multiple reaction monitoring mode with negative electrospray ionization at m/z 380→316 and 384→320 for celecoxib and the internal standard celecoxib-D₄, respectively. The lower limit of quantitation was 7.0 ng/ml using 0.1 ml of plasma and linearity was demonstrated up to 1800 ng/ml. Intra-assay and inter-assay precision expressed by relative standard deviation was less than 4% and inaccuracy did not exceed 6% at all levels. The assay was applied to the analysis of samples from a pharmacokinetic study.
- MeSH
- dospělí MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací metody MeSH
- inhibitory cyklooxygenasy 2 krev MeSH
- krevní plazma chemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- pyrazoly krev MeSH
- sulfonamidy krev MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- Publikační typ
- abstrakt z konference MeSH
A liquid chromatography-electrospray tandem mass spectrometry method was developed and validated to quantitate solifenacin in human plasma. The assay was based on protein precipitation with methanol and liquid chromatography performed on a pentafluorophenylpropylsilica column (50×4mm, 3μm particles), the mobile phase consisted of methanol - 100mM ammonium acetate containing 1% of formic acid (90:10, v/v). Quantification was through positive-ion mode and selected reaction monitoring at m/z 363→193 and 368→198 for solifenacin and the internal standard solifenacin-D(5), respectively. The lower limit of quantitation was 0.47ng/ml using 0.25ml of plasma and linearity was demonstrated up to 42ng/ml. Intra-assay and inter-assay precision expressed by relative standard deviation was less than 11% and inaccuracy did not exceed 11% at all levels. The assay was applied to the analysis of samples from a pharmacokinetic study.
- MeSH
- chinuklidiny krev chemie farmakokinetika MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- lineární modely MeSH
- reprodukovatelnost výsledků MeSH
- senzitivita a specificita MeSH
- stabilita léku MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- tetrahydroisochinoliny krev chemie farmakokinetika MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
A rapid and reliable method was developed to quantitate tolterodine and its 5-hydroxymethyl metabolite in human plasma using liquid chromatography-electrospray tandem mass spectrometry. The assay was based on liquid-liquid extraction of the compounds from plasma with tert-butylmethylether and hydrophilic interaction chromatography performed on a silica column (30mmx4.6mm, 3microm particles), the mobile phase consisted of acetonitrile-20mM ammonium acetate (70:30, v/v). Quantification was through positive-ion mode and selected reaction monitoring at m/z 326-->147 for tolterodine, 342-->223 for the 5-hydroxymethyl metabolite and 260-->183 for the internal standard propranolol, respectively. The lower limit of quantitation was 49 and 46pg/ml using 0.5ml of plasma for the parent drug and its metabolite, respectively and linearity was observed up to 30ng/ml. Within-day and between-day precision expressed by relative standard deviation was less than 11% and inaccuracy did not exceed 7% at all levels. The assay was applied to the analysis of samples from a pharmacokinetic study.
- MeSH
- benzhydrylové sloučeniny farmakokinetika chemie krev MeSH
- dospělí MeSH
- fenylpropanolamin farmakokinetika chemie krev MeSH
- kresoly farmakokinetika chemie krev MeSH
- lidé MeSH
- mladý dospělý MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
A high-performance liquid chromatographic method with fluorescence detection for the determination of itopride in human plasma is reported. The sample preparation was based on liquid-liquid extraction of itopride from plasma with t-butylmethylether and dichloromethane (70:30, v/v) mixture followed by a back extraction of the analyte to the phosphate buffer (pH 3.2). Liquid chromatography was performed on an octadecylsilica column (55 mm x 4 mm, 3 microm particles), the mobile phase consisted of acetonitrile-triethylamine-15 mM dihydrogenpotassium phosphate (14.5:0.5:85, v/v/v), pH of the mobile phase was adjusted to 4.8. The run time was 3 min. The fluorimetric detector was operated at 250/342 nm (excitation/emission wavelength). Naratriptan was used as the internal standard. The limit of quantitation was 9.5 ng/ml using 0.5 ml of plasma. The method precision and inaccuracy were less than 8%. The assay was applied to the analysis of samples from a bioequivalence study.
- MeSH
- benzamidy krev MeSH
- benzylové sloučeniny krev MeSH
- dospělí MeSH
- fluorometrie metody přístrojové vybavení MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- vysokoúčinná kapalinová chromatografie metody přístrojové vybavení MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
A sensitive and reliable method was developed to quantitate phenylephrine in human plasma using liquid chromatography-electrospray tandem mass spectrometry. The assay was based on solid-phase extraction with C18 cartridges and hydrophilic interaction chromatography performed on a pentafluorophenylpropylsilica column (50 mm x 4 mm, 3 microm particles), the mobile phase consisted of methanol-10 mM ammonium acetate (90:10, v/v). Quantification was through positive-ion mode and selected reaction monitoring at m/z 168.1-->135.0 for phenylephrine and m/z 182.1-->135.0 for internal standard etilefrin, respectively. The lower limit of quantitation was 51 pg/ml using 0.25 ml of plasma and linearity was observed from 51 to 5500 pg/ml. Within-day and between-day precision expressed by relative standard deviation was less than 12% and inaccuracy did not exceed 8% at all levels. The assay was applied to the analysis of samples from a pharmacokinetic study.
- MeSH
- agonisté adrenergních alfa-receptorů farmakokinetika krev MeSH
- chromatografie kapalinová metody MeSH
- fenylefrin farmakokinetika krev normy MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací metody MeSH
- lidé MeSH
- molekulární struktura MeSH
- referenční standardy MeSH
- reprodukovatelnost výsledků MeSH
- rozpouštědla chemie MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- validační studie MeSH
A rapid, sensitive and reliable method was developed to quantitate omeprazole in human plasma using liquid chromatography-tandem mass spectrometry. The assay is based on protein precipitation with acetonitrile and reversed-phase liquid chromatography performed on an octadecylsilica column (55 mm x 2mm, 3 microm particles), the mobile phase consisted of methanol-10 mM ammonium acetate (60:40, v/v). Omeprazole and flunitrazepam, the internal standard, elute at 0.80+/-0.10 min with a total run time 1.35 min. Quantification was through positive ion mode and selected reaction monitoring mode at m/z 346.1-->197.9 for omeprazole and m/z 314.0-->268.0 for flunitrazepam, respectively. The lower limit of quantitation was 1.2 ng/ml using 0.25 ml of plasma and linearity was observed from 1.2 to 1200 ng/ml. Within-day and between-day precision expressed by relative standard deviation was less than 5% and inaccuracy did not exceed 12%. The assay was applied to the analysis of samples from a pharmacokinetic study.
- MeSH
- hmotnostní spektrometrie metody MeSH
- inhibitory enzymů farmakokinetika krev MeSH
- krevní proteiny metabolismus MeSH
- lidé MeSH
- omeprazol farmakokinetika krev MeSH
- protivředové látky farmakokinetika krev MeSH
- referenční standardy MeSH
- reprodukovatelnost výsledků MeSH
- senzitivita a specificita MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- validační studie MeSH
