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Photodermatol Photoimmunol Photomed. 1996 Feb;12(1):1-6.
Phototoxicity due to sulphonamide derived oral antidiabetics and diuretics: investigations in a cell culture model.

Selvaag E, Anholt H, Moan J, Thune P.

Department of Dermatology, Ullevaal Hospital, University of Oslo, Norway.

A number of sulphonamide-derived oral antidiabetics (chlorpropamide, glibenclamide, glipizide, gliquidone, glymidine, tolazamide and tolbutamide) and diuretics (bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, chloratalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, piretanide, polythiazide, trichlormethiazide and xipamide) were investigated for phototoxicity in a cell culture model. Cell death dependent on ultraviolet A fluence and test substance concentration was observed in the presence of the oral antidiabetics glibenclamide and gliquidone, as well as the diuretics bemetizide, bendroflumethiazide, benzyl-hydrochlorothiazide, bumetanide, butizide, hydrochlorothiazide, hydroflumethiazide, piretanide, polythiazide and trichlormethiazide. Bendroflumethiazide was phototoxic at 5x10(-5) M and higher concentrations, bemetizide, benzylhydrochlorothiazide, bumetanide and hydroflumethiazide were phototoxic at 2.5x10(-4) M and higher concentrations, and the oral antidiabetics glibenclamide and gliquidone as well as the diuretics butizide, hydrochlorothiazide, piretanide, polythiazide and trichlormethiazide were phototoxic at 5(-4) M and higher concentrations. Electron microscopic investigations showed swelling of mitochondria and endoplasmic reticulum as well as aggregation of euchromatin when the cells were irradiated in the presence of photosensitizers.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8884891&dopt=Abstract

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BACKGROUND: The diagnosis of "factitious hypoglycemia" is essentially based on the disclosure of hypoglycemic agents in blood or urine. The aim of this study was to evaluate the performance of capillary electrophoresis (CE) as a quantitative method for determination of chlorpropamide, tolbutamide, glipizide, gliclazide, and glibenclamide in serum. METHODS: Serum samples (1 mL), with internal standard added, were purified by solid-phase extraction on OASIS(TM) HLB cartridges (Waters), dried under reduced pressure, and reconstituted with 30-60 microL of acetonitrile:H(2)O. Analysis was carried out by micellar electrokinetic capillary chromatography in 5 mmol/L borate, 5 mmol/L phosphate, 75 mmol/L sodium cholate, pH 8.5, containing 25 mL/L methanol. Separation was accomplished in a 20 cm x 50 microm (i.d.) silica capillary at 25 degrees C and a constant voltage of +10 kV. Pharmacokinetics of gliclazide (80-mg tablet) in a diabetic patient were assayed by both HPLC and CE. Two hypoglycemic patients positive by HPLC analysis for unreported gliclazide and tolbutamide overdose were also screened by CE. RESULTS: Separation of six drugs (including the internal standard) was accomplished in 5 min plus 5 min rinsing. The between-day CV of the ratio of the areas of the sulfonylurea drugs to internal standard was <1% (n = 10). Linearity (r(2) > or =0.998) and recovery (> or =80%) were good for all sulfonylurea drugs tested. Pharmacokinetic curves for gliclazide by CE and HPLC were superimposable. CE analysis confirmed the HPLC diagnosis of surreptitious abuse of gliclazide and tolbutamide. CONCLUSION: CE is a useful tool in the clinical chemistry and toxicology laboratory for drug monitoring and pharmacokinetic investigations.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11067812&dopt=Abstract




Pharmacotherapy. 1996 Sep-Oct;16(5):760-8.
The influence of multiple dosing and age on the pharmacokinetics and pharmacodynamics of glipizide in patients with type II diabetes mellitus.

Jaber LA, Ducharme MP, Edwards DJ, Slaughter RL, Grunberger G.

Department of Pharmacy Practice, Wayne State University, Detroit, Michigan 48201, USA.

STUDY OBJECTIVES: To determine the pharmacokinetics and pharmacodynamics of glipizide after a single dose and 12 weeks of dosing in patients with type II diabetes mellitus, and evaluate the influence of aging. DESIGN: Comparison of single and multiple doses of glipizide. SETTING: University-affiliated outpatient internal medicine clinic and diabetes care unit. PATIENTS: Twenty patients (11 men, 9 women, mean age 55.2 +/- 9.9 yrs) with type II diabetes mellitus who were currently receiving oral hypoglycemic agents or were hyperglycemic with diet. INTERVENTIONS: A 24-hour pharmacokinetic evaluation of glipizide was assessed after a 5-mg dose at the start of therapy and after 12 weeks of therapy. Pharmacokinetic parameters were assessed using compartmental population analysis techniques. Glipizide pharmacodynamic evaluation was assessed by serum glucose, insulin, and C-peptide responses during a 4-hour Sustacal tolerance test performed at baseline before instituting glipizide therapy, with the first 5-mg dose, and at week 12 of therapy. Glipizide dosages were titrated to a targeted goal of fasting plasma glucose of 7.8 mmol/L or less or to reach maximum daily doses of 40 mg. MEASUREMENTS AND MAIN RESULTS: No significant differences in time to peak concentration, apparent volumes of distribution for the central and peripheral compartments, apparent oral clearance from the central compartment, distributional clearance between the central and peripheral compartments, or terminal elimination half-life were observed with a single dose and long-term dosing. The mean +/- SD terminal elimination half-lives were 9.67 +/- 5.6 and 9.35 +/- 4.6 hours after a single dose and 12 weeks, respectively. Fasting plasma glucose concentrations decreased from 12.3 +/- 3.6 mmol/L before the first dose of glipizide to 9.2 +/- 1.7 mmol/L after 12 weeks of treatment. The values for area under the serum concentration-time curve from zero to 4 hours for glucose (AUC0-4.glucose) were significantly reduced at week 12 (baseline 49.8 +/- 15.6, week 12 37.8 +/- 9.8 mmol/L/hr). Glipizide provoked an increase in serum insulin and C-peptide concentrations (AUC0-4.insulin: baseline 698 +/- 327, single dose 954 +/- 461, long-term dosing 945 +/- 600 pmol/L/hr). No significant change in insulin response was observed between single and multiple doses. No age-related differences in the pharmacokinetic parameters or the pharmacodynamic responses of glipizide were observed. CONCLUSIONS: Long-term dosing and aging have little effect on the pharmacokinetic profile of glipizide. In addition, glipizide stimulates insulin secretion to a similar extent following glucose challenge after a single dose and long-term administration.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8888072&dopt=Abstract












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