scholarly journals Characterization of the In Vitro Inhibitory Potential of the Oligonucleotide Imetelstat on Human Cytochrome P450 Enzymes with Predictions of In Vivo Drug-Drug Interactions

2018 ◽  
Vol 47 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Faraz Kazmi ◽  
Carlo Sensenhauser ◽  
Tony Greway
Keyword(s):  
Cytochrome P450 ◽  
Drug Interactions ◽  
Cytochrome P450 Enzymes ◽  
Human Cytochrome ◽  
Inhibitory Potential

scholarly journals In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug–drug interactions

2020 ◽  
Vol 72 (3) ◽  
pp. 612-621 ◽  
Author(s):  
Jacek Wójcikowski ◽  
Przemysław J. Danek ◽  
Agnieszka Basińska-Ziobroń ◽  
Renata Pukło ◽  
Władysława A. Daniel
Keyword(s):  
Cytochrome P450 ◽  
Drug Interactions ◽  
Atypical Antipsychotic ◽  
Antipsychotic Drug ◽  
The Novel ◽  
Cytochrome P450 Enzymes ◽  
Atypical Antipsychotic Drug ◽  
Human Cytochrome ◽  
In Vitro Inhibition

scholarly journals Assessment of inhibitory effects on major human cytochrome P450 enzymes by spasmolytics used in the treatment of overactive bladder syndrome

2017 ◽  
Vol 9 (7) ◽  
pp. 163-177
Author(s):  
Dominik Dahlinger ◽  
Sevinc Aslan ◽  
Markus Pietsch ◽  
Sebastian Frechen ◽  
Uwe Fuhr
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Fold Increase ◽  
Pharmacokinetic Data ◽  
Cytochrome P450 Enzymes ◽  
Trospium Chloride ◽  
Screening Experiments ◽  
Human Cytochrome

Background: The objective of this study was to examine the inhibitory potential of darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium chloride on the seven major human cytochrome P450 enzymes (CYP) by using a standardized and validated seven-in-one cytochrome P450 cocktail inhibition assay. Methods: An in vitro cocktail of seven highly selective probe substrates was incubated with human liver microsomes and varying concentrations of the seven test compounds. The major metabolites of the probe substrates were simultaneously analysed using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Enzyme kinetics were estimated by determining IC50 and Ki values via nonlinear regression. Obtained Ki values were used for predictions of potential clinical impact of the inhibition using a static mechanistic prediction model. Results: In this study, 49 IC50 experiments were conducted. In six cases, IC50 values lower than the calculated threshold for drug–drug interactions (DDIs) in the gut wall were observed. In these cases, no increase in inhibition was determined after a 30 min preincubation. Considering a typical dosing regimen and applying the obtained Ki values of 0.72 µM (darifenacin, 15 mg daily) and 7.2 µM [propiverine, 30 mg daily, immediate release (IR)] for the inhibition of CYP2D6 yielded a predicted 1.9-fold and 1.4-fold increase in the area under the curve (AUC) of debrisoquine (CYP2D6 substrate), respectively. Due to the inhibition of the particular intestinal CYP3A4, the obtained Ki values of 14 µM of propiverine (30 mg daily, IR) resulted in a predicted doubling of the AUC for midazolam (CYP3A4 substrate). Conclusions: In vitro/ in vivo extrapolation based on pharmacokinetic data and the conducted screening experiments yielded similar effects of darifenacin on CYP2D6 and propiverine on CYP3A4 as obtained in separately conducted in vivo DDI studies. As a novel finding, propiverine was identified to potentially inhibit CYP2D6 at clinically occurring concentrations.

scholarly journals Prediction of seriniquinone-drug interactions by in vitro inhibition of human cytochrome P450 enzymes

2020 ◽  
Vol 65 ◽  
pp. 104820
Author(s):  
Rodrigo Moreira da Silva ◽  
Daniel Blascke Carrão ◽  
Maísa Daniela Habenschus ◽  
Paula Christine Jimenez ◽  
Norberto Peporine Lopes ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Interactions ◽  
Cytochrome P450 Enzymes ◽  
Human Cytochrome ◽  
In Vitro Inhibition

scholarly journals Highly Miniaturized Formats for In Vitro Drug Metabolism Assays Using Vivid® Fluorescent Substrates and Recombinant Human Cytochrome P450 Enzymes

2005 ◽  
Vol 10 (1) ◽  
pp. 56-66 ◽  
Author(s):  
Olga V. Trubetskoy ◽  
Jasmin R. Gibson ◽  
Bryan D. Marks
Keyword(s):  
Cytochrome P450 ◽  
High Throughput Screening ◽  
Cytochrome P450 Enzymes ◽  
Fluorogenic Substrates ◽  
Detailed Characterization ◽  
Human Cytochrome ◽  
Screening Assays ◽  
Well Assay

Highly miniaturized P450 screening assays designed to enable facile analysis of P450 drug interactions in a 1536-well plate format with the principal human cytochrome P450 enzymes (CYP3A4, 2D6, 2C9, 2C19, and 1A2) and Vivid® fluorogenic substrates were developed. The detailed characterization of the assays included stability, homogeneity, and reproducibility of the recombinant P450 enzymes and the kinetic parameters of their reactions with Vivid® fluorogenic substrates, with a focus on the specific characteristics of each component that enable screening in a low-volume 1536-well plate assay format. The screening assays were applied for the assessment of individual cytochrome P450 inhibition profiles with a panel of selected assay modifiers, including isozyme-specific substrates and inhibitors. IC50 values obtained for the modifiers in 96- and 1536-well plate formats were similar and comparable with values obtained in assays with conventional substrates. An overall examination of the 1536-well assay statistics, such as signal-to-background ratio and Z′ factor, demonstrated that these assays are a robust, successful, and reliable tool to screen for cytochrome P450 metabolism and inhibition in an ultra-high-throughput screening format. ( Journal of Biomolecular Screening 2005:56-66)

scholarly journals Characterization of human cytochrome P450 enzymes catalyzing domperidone N-dealkylation and hydroxylation in vitro

2004 ◽  
Vol 58 (3) ◽  
pp. 277-287 ◽  
Author(s):  
Bryan A. Ward ◽  
Alan Morocho ◽  
Abdullah Kandil ◽  
Raymond E. Galinsky ◽  
David A. Flockhart ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 Enzymes ◽  
Human Cytochrome

scholarly journals Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters

2020 ◽  
Vol 21 (14) ◽  
pp. 1127-1135
Author(s):  
Slobodan Rendic ◽  
Frederick Peter Guengerich
Keyword(s):  
Cytochrome P450 ◽  
Inflammatory Diseases ◽  
Drug Transporters ◽  
Transport Systems ◽  
Cytochrome P450 Enzymes ◽  
Human Cytochrome ◽  
Metabolic Properties ◽  
P450 2D6

Background:: In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients. Methods:: Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/) and the ADME database (https://life-science.kyushu.fujitsu.com/admedb/). Results:: Chloroquine and hydroxychloroquine are metabolized by P450 1A2, 2C8, 2C19, 2D6, and 3A4/5 in vitro and by P450s 2C8 and 3A4/5 in vivo by N-deethylation. Chloroquine effectively inhibited P450 2D6 in vitro; however, in vivo inhibition was not apparent except in individuals with limited P450 2D6 activity. Chloroquine is both an inhibitor and inducer of the transporter MRP1 and is also a substrate of the Mate and MRP1 transport systems. Hydroxychloroquine also inhibited P450 2D6 and the transporter OATP1A2. Conclusions:: Chloroquine caused a statistically significant decrease in P450 2D6 activity in vitro and in vivo, also inhibiting its own metabolism by the enzyme. The inhibition indicates a potential for clinical drug-drug interactions when taken with other drugs that are predominant substrates of the P450 2D6. When chloroquine and hydroxychloroquine are used clinically with other drugs, substrates of P450 2D6 enzyme, attention should be given to substrate-specific metabolism by P450 2D6 alleles present in individuals taking the drugs.

In vitro inhibitory mechanisms and molecular docking of 1′-S-1′-acetoxychavicol acetate on human cytochrome P450 enzymes

Phytomedicine ◽  
2017 ◽  
Vol 31 ◽  
pp. 1-9 ◽  
Author(s):  
A.K.M. Mahmudul Haque ◽  
Kok Hoong Leong ◽  
Yoke Lin Lo ◽  
Khalijah Awang ◽  
Noor Hasima Nagoor
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Cytochrome P450 Enzymes ◽  
Inhibitory Mechanisms ◽  
Human Cytochrome
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