Assessing and minimizing time-dependent inhibition of cytochrome P450 3A in drug discovery: A case study with melanocortin-4 receptor agonists

Xenobiotica ◽  
2008 ◽  
Vol 38 (11) ◽  
pp. 1437-1451 ◽  
Author(s):  
W. Tang ◽  
R. A. Stearns ◽  
R. W. Wang ◽  
R. R. Miller ◽  
Q. Chen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Discovery ◽  
Time Dependent ◽  
Cytochrome P450 3A ◽  
Receptor Agonists ◽  
Melanocortin 4 Receptor ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition

scholarly journals Inhibition of Human Liver Cytochrome P450 by Star Fruit Juice

2007 ◽  
Vol 10 (4) ◽  
pp. 496 ◽  
Author(s):  
Jiang-Wei Zhang ◽  
Yong Liu ◽  
Jie Cheng ◽  
Wei Li ◽  
Hong Ma ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Fruit Juice ◽  
Liver Microsomes ◽  
Time Dependent ◽  
Inhibitory Effects ◽  
Star Fruit ◽  
Dependent Inhibition ◽  
Cyp Isoforms ◽  
Time Dependent Inhibition

Purpose. To examine the inhibitory effects of star fruit (Averrhoa carambola) juice towards seven major cytochrome P450 (CYP) isoforms and NADPH-cytochrome P450 reductase (CPR). Methods. The inhibitory effects of star fruit juice (0.5 to 5%, v/v) against the activities of seven CYP isoforms including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4 and CPR were examined in human liver microsomes. To identify time-dependent inhibition, star fruit juice (2.5%, v/v) was preincubated with microsomes and a NADPH-generating system for 0-15 min, and then the extent of inhibition towards seven CYP isoforms were examined. Results. Star fruit juice (5.0%, v/v) was found to inhibit all the activities of CYP isoforms tested by more than 70%. Based on the half inhibition values (%, v/v), the inhibitory effects towards different CYP isoforms were in the following order: CYP2A6 (0.9) > CYP1A2 (1.4) > CYP2D6 (1.6) > CYP2E1 (2.0) > CYP2C8 (2.2) > CYP2C9 (3.0) > CYP3A4 (3.2). Time-dependent inhibition was not observed towards any of the tested CYP isoforms. In addition, star fruit juice was found not to inhibit the activity of CPR. Conclusions. Star fruit juice inhibited the seven CYP isoforms tested, with the strongest inhibitory effect against CYP2A6 and the least towards CYP3A4.

Integrated in Silico−in Vitro Strategy for Addressing Cytochrome P450 3A4 Time-Dependent Inhibition

2010 ◽  
Vol 23 (3) ◽  
pp. 664-676 ◽  
Author(s):  
Michael Zientek ◽  
Chad Stoner ◽  
Robyn Ayscue ◽  
Jacquelyn Klug-McLeod ◽  
Ying Jiang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Silico ◽  
Time Dependent ◽  
Cytochrome P450 3A4 ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition

scholarly journals Time‐dependent Inhibition of Cytochrome P450 2A13 (CYP2A13): by Cinnamaldehyde as a Lung Cancer Preventive Agent

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Brandon S. San ◽  
Isabelle Wong ◽  
Jeffery Li ◽  
Aiden Nguyen ◽  
John Harrelson
Keyword(s):  
Lung Cancer ◽  
Cytochrome P450 ◽  
Time Dependent ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition

scholarly journals Mechanistic Studies of Cytochrome P450 3A4 Time-Dependent Inhibition Using Two Cysteine-Targeting Electrophiles

2020 ◽  
Vol 48 (6) ◽  
pp. 508-514
Author(s):  
John T. Barr ◽  
Zhican Wang ◽  
Xiaoshan Min ◽  
Henry J. Wienkers ◽  
Brooke M. Rock ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Time Dependent ◽  
Cytochrome P450 3A4 ◽  
Mechanistic Studies ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition
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