Halogen Substitution Influences Ketamine Metabolism by Cytochrome P450 2B6: In Vitro and Computational Approaches

2018 ◽  
Vol 16 (2) ◽  
pp. 898-906 ◽  
Author(s):  
Pan-Fen Wang ◽  
Alicia Neiner ◽  
Thomas R. Lane ◽  
Kimberley M. Zorn ◽  
Sean Ekins ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Computational Approaches ◽  
Cytochrome P450 2B6

scholarly journals Comparison of In Vitro Metabolism of Ticlopidine by Human Cytochrome P450 2B6 and Rabbit Cytochrome P450 2B4

2010 ◽  
Vol 39 (3) ◽  
pp. 539-550 ◽  
Author(s):  
Jyothi C. Talakad ◽  
Manish B. Shah ◽  
Gregory S. Walker ◽  
Cathie Xiang ◽  
James R. Halpert ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Vitro Metabolism ◽  
Cytochrome P450 2B6 ◽  
Human Cytochrome ◽  
Cytochrome P450 2B4

Evaluation of 227 Drugs for In Vitro Inhibition of Cytochrome P450 2B6

2006 ◽  
Vol 46 (12) ◽  
pp. 1426-1438 ◽  
Author(s):  
Robert L. Walsky ◽  
Angela V. Astuccio ◽  
R. Scott Obach
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 2B6 ◽  
In Vitro Inhibition

scholarly journals Potential Contribution of Cytochrome P450 2B6 to Hepatic 4-Hydroxycyclophosphamide Formation In Vitro and In Vivo

2011 ◽  
Vol 40 (1) ◽  
pp. 54-63 ◽  
Author(s):  
Brianne S. Raccor ◽  
Adam J. Claessens ◽  
Jean C. Dinh ◽  
Julie R. Park ◽  
Douglas S. Hawkins ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Potential Contribution ◽  
Cytochrome P450 2B6

scholarly journals Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers

2016 ◽  
Vol 60 (11) ◽  
pp. 6813-6822 ◽  
Author(s):  
Zeruesenay Desta ◽  
Ingrid F. Metzger ◽  
Nancy Thong ◽  
Jessica B. L. Lu ◽  
John T. Callaghan ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Healthy Volunteers ◽  
Quantitative Estimation ◽  
Formation Rate ◽  
Transcriptase Inhibitor ◽  
Time Curve ◽  
Cytochrome P450 2B6 ◽  
Plasma Concentration Ratio

ABSTRACTCytochrome P450 2B6 (CYP2B6) metabolizes clinically important drugs and other compounds. Its expression and activity vary widely among individuals, but quantitative estimation is hampered by the lack of safe and selectivein vivoprobes of CYP2B6 activity. Efavirenz, a nonnucleoside HIV-1 reverse transcriptase inhibitor, is mainly cleared by CYP2B6, an enzyme strongly inhibitedin vitroby voriconazole. To test efavirenz metabolism as anin vivoprobe of CYP2B6 activity, we quantified the inhibition of CYP2B6 activity by voriconazole in 61 healthy volunteers administered a single 100-mg oral dose of efavirenz with and without voriconazole administration. The kinetics of efavirenz metabolites demonstrated formation rate-limited elimination. Compared to control, voriconazole prolonged the elimination half-life (t1/2) and increased both the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve from 0 h tot(AUC0–t) of efavirenz (mean change of 51%, 36%, and 89%, respectively) (P< 0.0001) with marked intersubject variability (e.g., the percent change in efavirenz AUC0–tranged from 0.4% to ∼224%). Voriconazole decreased efavirenz 8-hydroxylation by greater than 60% (P< 0.0001), whereas its effect on 7-hydroxylation was marginal. The plasma concentration ratio of efavirenz to 8-hydroxyefavirenz, determined 1 to 6 h after dosing, was significantly increased by voriconazole and correlated with the efavirenz AUC0–t(Pearsonr= >0.8;P< 0.0001). This study demonstrates the mechanisms of voriconazole-efavirenz interaction, establishes the use of a low dose of efavirenz as a safe and selectivein vivoprobe for phenotyping CYP2B6 activity, and identifies several easy-to-use indices that should enhance understanding of the mechanisms of CYP2B6 interindividual variability. (This study is registered at ClinicalTrials.gov under identifier NCT01104376.)

Measurement of In Vitro Cytochrome P450 2B6 Activity

2009 ◽  
Vol 39 (1) ◽  
Author(s):  
Robert L. Walsky ◽  
R. Scott Obach
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 2B6

The Molecular and Enzyme Kinetic Basis for Altered Activity of Three Cytochrome P450 2C19 Variants Found in the Chinese Population

2020 ◽  
Vol 13 (3) ◽  
pp. 233-244
Author(s):  
Amelia Nathania Dong ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Beow Chin Yiap ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Active Site ◽  
Chinese Population ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
In Vitro Assays ◽  
Access Channel ◽  
Cytochrome P450 2C19

Background: There is a large inter-individual variation in cytochrome P450 2C19 (CYP2C19) activity. The variability can be caused by the genetic polymorphism of CYP2C19 gene. This study aimed to investigate the molecular and kinetics basis for activity changes in three alleles including CYP2C19*23, CYP2C19*24 and CYP2C19*25found in the Chinese population. Methods: The three variants expressed by bacteria were investigated using substrate (omeprazole and 3- cyano-7-ethoxycoumarin[CEC]) and inhibitor (ketoconazole, fluoxetine, sertraline and loratadine) probes in enzyme assays along with molecular docking. Results: All alleles exhibited very low enzyme activity and affinity towards omeprazole and CEC (6.1% or less in intrinsic clearance). The inhibition studies with the four inhibitors, however, suggested that mutations in different variants have a tendency to cause enhanced binding (reduced IC50 values). The enhanced binding could partially be explained by the lower polar solvent accessible surface area of the inhibitors relative to the substrates. Molecular docking indicated that G91R, R335Q and F448L, the unique mutations in the alleles, have caused slight alteration in the substrate access channel morphology and a more compact active site cavity hence affecting ligand access and binding. It is likely that these structural alterations in CYP2C19 proteins have caused ligand-specific alteration in catalytic and inhibitory specificities as observed in the in vitro assays. Conclusion: This study indicates that CYP2C19 variant selectivity for ligands was not solely governed by mutation-induced modifications in the active site architecture, but the intrinsic properties of the probe compounds also played a vital role.

Effect of Commonly Used Organic Solvents on the Kinetics of Cytochrome P450 2B6- and 2C8-Dependent Activity in Human Liver Microsomes

2007 ◽  
Vol 35 (11) ◽  
pp. 1990-1995 ◽  
Author(s):  
Ragini Vuppugalla ◽  
Shu-Ying Chang ◽  
Hongjian Zhang ◽  
Punit H. Marathe ◽  
David A. Rodrigues
Keyword(s):  
Cytochrome P450 ◽  
Organic Solvents ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Cytochrome P450 2B6 ◽  
Dependent Activity ◽  
Kinetics Of

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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