- Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity
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Ketoconazole (KC), an antifungal agent, rarely causes severe liver injury when orally administered. It has been reported that KC is mainly hydrolyzed to N-deacetyl ketoconazole (DAK), followed by the N-hydroxylation of DAK by flavin-containing monooxygenase (FMO). Although the metabolism of KC has been considered to be associated with hepatotoxicity, the responsible enzyme(s) remain unknown. The purpose of this study was to identify the responsible enzyme(s) for KC hydrolysis in humans and to clarify their relevance to KC-induced toxicity. Kinetic analysis and inhibition studies using human liver microsomes (HLM) and recombinant enzymes revealed that human arylacetamide deacetylase (AADAC) is responsible for KC hydrolysis to form DAK, and confirmed that FMO3 is the enzyme responsible for DAK N-hydroxylation. In HLM, the clearance of KC hydrolysis occurred to the same extent as DAK N-hydroxylation, which indicates that both processes are not rate-limiting pathways. Cytotoxicity of KC and DAK was evaluated using HepaRG cells and human primary hepatocytes. Treatment of HepaRG cells with DAK for 24?h showed cytotoxicity in a dose-dependent manner, whereas treatment with KC did not show due to the low expression of AADAC. Overexpression of AADAC in HepaRG cells with an adenovirus expression system elicited the cytotoxicity of KC. Cytotoxicity of KC in human primary hepatocytes was attenuated by diisopropylfluorophosphate, an AADAC inhibitor. In conclusion, the present study demonstrated that human AADAC hydrolyzes KC to trigger hepatocellular toxicity.
- Fukami, Tatsuki,Iida, Azumi,Konishi, Keigo,Nakajima, Miki
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- Stereoselective determination of the epimer mixtures of itraconazole in human blood plasma using HPLC and fluorescence detection
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Itraconazole is an antifungal drug widely used in a variety of fungal infections, which have become a significant public-health problem in recent decades. Itraconazole is a chiral drug consisting of two diastereoisomeric racemates, i.e., four stereoisomers. Data in the literature suggests that stereochemistry may play a significant role in the action and disposition of the drug and therefore stereoselective analytical methods for the determination of the drug in biological fluids are needed for the elucidation of that role. We report a stereoselective HPLC method that incorporates solvent extraction, the use of an internal standard, two chiral stationary phases in series, and fluorescence detection. The procedure is enantioselective and partially diastereoselective and provides the concentrations in blood plasma of the two epimer mixtures 2R,4S,2'R/2R,4S2'S and 2S,4R,2'R/2S,4R,2'S, respectively, each of which is a combination of the two epimers that differ in the configuration at the sec-butyl group. The analytical method has suitable sensitivity, recovery, precision, and accuracy. Analysis of the plasma of a human subject six hours after the oral administration of a single 200-mg dose of itraconazole showed a 3.4-fold difference between the concentrations of the epimer mixtures. The method has certain advantages over the published alternative procedure that uses LC-MS. Copyright
- Pyrgaki, Christina,Bannister, Steve J.,Gera, Lajos,Gerber, John G.,Gal, Joseph
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p. 495 - 503
(2012/01/11)
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- NO-donors. Part 171: Synthesis and antimicrobial activity of novel ketoconazole-NO-donor hybrid compounds
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Novel hybrid compounds combining the antifungal drug ketoconazole with a diazen-1-ium-1,2-diolate or an organic nitrate moiety and the corresponding NO-donors without ketoconazole were synthesized and their activities against a broad variety of fungal strains were tested. Hybridization modifies the spectrum of antimicrobial activities and generally, the ketoconazole-NO-donor hybrids are more potent than ketoconazole. The NO-donors alone show insufficient effectiveness.
- Konter, Joerg,Moellmann, Ute,Lehmann, Jochen
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p. 8294 - 8300
(2008/12/23)
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- Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones
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A series of novel triazol-3-ones has been synthesized, and their in vitro and in vivo antifungal properties are reported. Traconazole. which displays a pronounced oral activity against vaginal candidosis in rats and against microsporosis in guinea pigs, has been selected for clinical evaluation.
- Heeres,Backx,Van Cutsem
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p. 894 - 900
(2007/10/02)
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