Analytical approaches to determine cytochrome P450 inhibitory potential of new chemical entities in drug discovery

Smith, Danielle; Sadagopan, Nalini; Zientek, Michael; Reddy, A. Rajasekhar; Cohen, Lee M.

doi:10.1016/j.jchromb.2006.12.024

Cited by 50 publications

(28 citation statements)

References 35 publications

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“…Определение активности различных изоформ цитохромов Р450 осуществляется на основании количества образующегося продукта реакции, при этом для детекции используется в основном масс-спектрометр с тройным квадруполем (QQQ) [74][75][76][77][78][79][80][81][82][83][84][85][86][87]. QQQ состоит из двух квадруполей и находящейся между ними ячейки соударений.…”

Section: методы основанные на вэжх с ультрафиолетовым и масс-спектроunclassified

“…Наличие двух фильтров позволяет получить селективный сигнал исследуемого вещества и повысить чувствительность определения. Анализ литературных данных о наиболее часто используемых субстратах цитохромов Р450 и масс-спектрометрических параметрах, используемых для детектирования суммирован в таблице 3 [74][75][76][77][78][79][80][81][82][83][84][85][86][87].…”

Section: методы основанные на вэжх с ультрафиолетовым и масс-спектроunclassified

“…Например, в статьях [74][75][76][77][78][79][80][81][82] для исследования активности изоформы 1А2 в качестве субстрата использован фенацетин, а его метаболита -ацетоминофен. После инкубации пробы с фенацетином авторы статей [74][75][76][77][78][79][80][81][82] проводили анализ методом обращенно-фазовой жидкостной хроматографии с ионизацией в электроспрее и масс-спектрометрическим детектированием.…”

Section: методы основанные на вэжх с ультрафиолетовым и масс-спектроunclassified

“…После инкубации пробы с фенацетином авторы статей [74][75][76][77][78][79][80][81][82] проводили анализ методом обращенно-фазовой жидкостной хроматографии с ионизацией в электроспрее и масс-спектрометрическим детектированием. Для QQQ в качестве родительского использовали ион [М+Н]+ с m/z 152 Da, соответствующий протонированной форме фенацетина, а в качестве дочернего -фрагмент с m/z 110 Da.…”

Section: методы основанные на вэжх с ультрафиолетовым и масс-спектроunclassified

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Current methods of cytochrome P450 analysis

2012

BIOMED KHIM

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Current review describes recent approaches of cytochrome P450 concentration and activity evaluation. Special attention paid to modern methods of proteomic analysis such as electrophoresis and chromato-mass-spectrometry. Methods of targeted proteomic applicable for quantitative and qualitative study of P450s in biological samples as well as methods for the enzyme activity measurements are reviewed. Finally, data on correlation between certain P450 isoform content and its specific enzymatic activities were described and discussed in the review.

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Section: методы основанные на вэжх с ультрафиолетовым и масс-спектроunclassified

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Current methods of cytochrome P450 analysis

2012

BIOMED KHIM

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“…Here, we evaluated the effect of SC on the CYP450 system using the 'cocktail' approach, which involves multiple probe drugs. This approach has been widely used to monitor the influence of drugs on the P450 activities and potential drug-drug or herb-drug interactions [27][28][29][30]. The activity of drug metabolism enzymes can be assessed in vivo by the use of specific probe drugs [31].…”

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confidence: 99%

Effects of Unprocessed Versus Vinegar-Processed Schisandra chinensis on the Activity of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 Enzymes in Rats

Su¹,

Wang²,

Li³

et al. 2017

J Anal Bioanal Tech

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Schisandra chinensis (SC) is a well-known traditional Chinese herbal medicine that has been used in clinical practices for thousands of years. However, the differences between the effects of unprocessed and vinegarprocessed Schisandra chinensis (VSC) on cytochrome P450 (CYP450) activities are poorly understood. To evaluate the differences between processed and unprocessed SC on the metabolism of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 substrates in rats using a cocktail method based on a developed and validated high performance liquid chromatography-mass spectrometry (HPLC-MS) method. Six probe substrates (coumarin (CYP2A6), bupropion (CYP2B6), paclitaxel (CYP2C8), tolbutamide (CY2C9), omeprazole (CYP2C19) and metoprolol (CYP2D6)) were delivered simultaneously into rats treated with single or multiple doses of processed or crude SC extract. The plasma concentrations of the six probes were profiled by HPLC-MS, and their corresponding pharmacokinetic parameters were calculated. Treatment with single or multiple doses of either extract of SC or VSC induced CYP2A6, CYP2B6 and CYP2C9 enzyme activity and inhibited CYP2D6, CYP2C19 and CYP2C8 enzyme activity in rats. Furthermore, the inhibitory or induced effect of multiple doses of SC was more potent after vinegar processing than without vinegar processing. CYP2A6, 2B6 and 2C9 enzyme activity were induced significantly after treatment with multiple doses but not after a single dose. CYP2C19 enzyme activity were inhibited significantly after treatment with multiple doses but not after a single dose. These results provide useful scientific data for the safe clinical application of either extract of SC in combination with other drugs, which should lack the side effects induced by other herb-drug interactions.

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Enzyme Inhibition and Inactivation: Cytochrome P450 Enzymes

Obach

2009

Enzyme Inhibition in Drug Discovery and Development

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Analytical approaches to determine cytochrome P450 inhibitory potential of new chemical entities in drug discovery

Cited by 50 publications

References 35 publications

Current methods of cytochrome P450 analysis

Current methods of cytochrome P450 analysis

Effects of Unprocessed Versus Vinegar-Processed Schisandra chinensis on the Activity of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 Enzymes in Rats

Enzyme Inhibition and Inactivation: Cytochrome P450 Enzymes

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