Comparison of capillary zone electrophoresis and high performance liquid chromatography methods for quantitative determination of ketoconazole in drug formulations

Velikinac, Ivan; Čudina, Olivera; Janković, Ivana A.; Agbaba, Danica; Vladimirov, Sote

doi:10.1016/j.farmac.2003.11.019

Cited by 26 publications

(12 citation statements)

References 17 publications

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“…Ketoconazole (KTZ) was the first introduced orally administered azole. However, due to the risk of KTZ-induced hepatotoxicity and serious drug-drug interactions, its use tends to be restricted to serious infections resistant to other safer azoles (Velikinac et al, 2004;Korashy et al, 2007). KTZ,-2-(1H-imidazol-1-ylmethyl)-1,3dioxolan-4-yl]methoxy]phenyl]-piperazine, is a chiral drug administered clinically as a racemic (1:1) mixture of the enantiomers of the cis configuration (Fig.…”

Section: Introductionmentioning

confidence: 99%

A stereospecific high‐performance liquid chromatographic assay for the determination of ketoconazole enantiomers in rat plasma

Hamdy

Brocks

2008

Biomedical Chromatography

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A stereospecific high-performance liquid chromatographic assay was developed for the quantitation of ketoconazole enantiomers (KTZ) in rat plasma. After protein precipitation of 100 microL plasma using acetonitrile, a wash step was performed using hexane. The supernatant was removed and KTZ enantiomers and amiodarone, the internal standard, were extracted using liquid-liquid extraction with tert-butyl methyl ether. After transfer and evaporation of the organic layer, the residue was reconstituted in mobile phase and injected into the HPLC through a chiral column. The mobile phase consisted of hexane:ethanol:2-propanol with diethyl amine, pumped at 1.5 mL/min. All components eluted within 18 min. KTZ enantiomers were baseline resolved and peaks were symmetrical in appearance with no interferences. Calibration curves were linear over the range 62.5-5000 ng/mL of enantiomer. The intraday and interday CV% assessments were

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Section: Introductionmentioning

confidence: 99%

A stereospecific high‐performance liquid chromatographic assay for the determination of ketoconazole enantiomers in rat plasma

Hamdy

Brocks

2008

Biomedical Chromatography

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“…[2][3][4] Owing to the risk of KTZ-induced hepatotoxicity and serious drug-drug interactions, the use of KTZ as an antifungal agent tends to be restricted to more serious infections that are resistant to other safer azoles. 5,6 Because of its CYP inhibitory properties, KTZ is extensively used as a CYP and P-glycoprotein modulator for in vitro and in vivo drug interaction studies. [7][8][9][10][11] Surprisingly, the pharmacokinetic information pertaining to KTZ is relatively limited.…”

mentioning

confidence: 99%

Nonlinear stereoselective pharmacokinetics of ketoconazole in rat after administration of racemate

Hamdy

Brocks

2008

Chirality

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The stereoselective pharmacokinetics of ketoconazole (KTZ) enantiomers were studied in rat after i.v. and oral administration of (+/-)-KTZ. Sprague-Dawley rats were administered racemic KTZ as 10 mg/kg i.v. or orally over the range 10-80 mg/kg as single doses. Serial blood samples were collected over a 24-h period via surgically placed jugular vein cannulae. Plasma was assayed for KTZ enantiomer concentrations using stereospecific HPLC. Enantiomeric plasma protein binding was determined using an erythrocyte partitioning method at racemic concentrations of 10 and 40 mg/L. Stereoselective metabolism was tested by incubating the racemate (0.5-250 microM) with rat liver microsomes. In all rats, (+)-KTZ plasma concentrations were higher (up to 2.5-fold) than (-)-KTZ. The clearance and volume of distribution of the (-) enantiomer were approximately twofold higher than antipode. Half-life did not differ between the enantiomers. After oral doses the t(max) was not stereoselective. For both enantiomers with higher doses the respective half-life were found to increase. The mean unbound fraction of the (-) enantiomer was found to be up to threefold higher than that of the (+) enantiomer. At higher concentrations nonlinearity in plasma protein binding was observed for both enantiomers. There was no evidence of stereoselective metabolism by liver microsomes. Stereoselectivity in KTZ pharmacokinetics is attributable to plasma protein binding, although other processes such as transport or intestinal metabolism may also contribute.

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“…The methanolic extract is evaporated to dryness at 45°C under a gentle stream of nitrogen. The residue is reconstituted in 200 μL methanol after ultrasonication, filtrated from 0.45 μm pore sized membrane filter, and injected into the chromatographic column (Swezey et al, 1982;Riley, 1986;Pietra et al, 1992;Velikinac et al, 2004). The drug serum levels were determined by HPLC method.…”

Section: Methodsmentioning

confidence: 99%

In vitro and in vivo evaluation of oral tablet formulations prepared with ketoconazole and hydroxypropyl-β-cyclodextrin

2010

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Comparison of capillary zone electrophoresis and high performance liquid chromatography methods for quantitative determination of ketoconazole in drug formulations

Cited by 26 publications

References 17 publications

A stereospecific high‐performance liquid chromatographic assay for the determination of ketoconazole enantiomers in rat plasma

A stereospecific high‐performance liquid chromatographic assay for the determination of ketoconazole enantiomers in rat plasma

Nonlinear stereoselective pharmacokinetics of ketoconazole in rat after administration of racemate

In vitro and in vivo evaluation of oral tablet formulations prepared with ketoconazole and hydroxypropyl-β-cyclodextrin

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