In vitro assessment of cytochrome P450 inhibition: Strategies for increasing LC/MS‐based assay throughput using a one‐point IC50 method and multiplexing high‐performance liquid chromatography

Tong, Lin; Pan, Kristine; Mordenti, Joyce; Pan, Lin

doi:10.1002/jps.20884

Cited by 49 publications

(29 citation statements)

References 19 publications

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“…SFZ, a positive control, significantly suppressed the PHT metabolism by 1.0 mM and the IC50 value was estimated to be 0.3-1.0 mM. The IC50 value for SFZ on the CYP2C9 inhibition was reported in the range of 0.1-1.0 mM [11][12][13] , and therefore, we think that the present assay was valid. As to CrJ, its extract also concentration-dependently inhibited the PHT metabolism and the IC50 value was estimated to be 0.3-1.0％, which is similar to that in the previous assay.…”

Section: Discussionmentioning

confidence: 77%

The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

Ushijima

Koshimizu

Fujimura

2009

Jpn. J. Clin. Pharmacol. Ther.

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CYP2C9 is involved in the metabolism of many drugs such as warfarin and phenytoin（PHT). It is well known that some foods cause pharmacokinetic alterations of drugs and lead to toxicity. Regarding the interaction caused by cranberry juice（CrJ), its influence on the metabolism of warfarin, a CYP2C9 substrate, is controversial. In addition, information concerning the influence of CrJ on the pharmacokinetics of other substrate drugs of CYP2C9 is not available. To examine the inhibitory effect of CrJ on the metabolism of PHT, we performed experiments using a baculovirus expression microsome system and human liver microsome assay. CrJ concentration-dependently inhibited the substrate metabolism both in a baculovirus-expressed microsome system and in human liver microsome assay. These data support the idea that CrJ inhibits CYP2C9 activity, and the subsequent metabolism of drugs metabolized by CYP2C9. In this study, we did not identify the specific substance(s）which inhibits CYP2C9 activity. However, as CrJ did not enhance the PHT accumulation in 3D-HepG2 cells, it is thought that the penetration into hepatic cells of inhibitory substances in CrJ seems to be small.

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Section: Discussionmentioning

confidence: 77%

The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

Ushijima

Koshimizu

Fujimura

2009

Jpn. J. Clin. Pharmacol. Ther.

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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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In Vitro Liver Systems to Study Induction/Inhibition: Prediction of In Vivo Metabolism and Drug–Drug Interactions

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2012

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This chapter was the review focused on the evaluation systems for metabolic stability, CYP inhibition and induction not only in the selection process of development candidates including lead optimizations in drug discovery but also to support a design of clinical studies in drug development. In the former process, the advanced in vitro systems have been developed, associating with an inevitable paradigm shift from the throughput to the quality. The similar trend has been gradually transmitted to the prediction of clearance and DDI. The predictions appeared to be in the movement from the basic models to the more mechanistic models including PBPK.

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In vitro assessment of cytochrome P450 inhibition: Strategies for increasing LC/MS‐based assay throughput using a one‐point IC50 method and multiplexing high‐performance liquid chromatography

Cited by 49 publications

References 19 publications

The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

Current methods of cytochrome P450 analysis

In Vitro Liver Systems to Study Induction/Inhibition: Prediction of In Vivo Metabolism and Drug–Drug Interactions

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