Cytochrome P450 3A Time-Dependent Inhibition Assays are Too Sensitive for Identification of Drugs Causing Clinically Significant Drug-Drug Interactions: A Comparison of Human Liver Microsomes and Hepatocytes and Definition of Boundaries for Inactivation Rate Constants

2021 ◽  
pp. DMD-AR-2021-000356
Author(s):  
Heather Eng ◽  
Elaine Tseng ◽  
Matthew A. Cerny ◽  
Theunis C. Goosen ◽  
R. Scott Obach
Keyword(s):  
Cytochrome P450 ◽  
Rate Constants ◽  
Human Liver ◽  
Liver Microsomes ◽  
Time Dependent ◽  
Cytochrome P450 3A ◽  
Dependent Inhibition ◽  
Clinically Significant ◽  
Definition Of ◽  
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.

scholarly journals Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1419
Author(s):  
Seung-Bae Ji ◽  
So-Young Park ◽  
Subin Bae ◽  
Hyung-Ju Seo ◽  
Sin-Eun Kim ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Human Liver ◽  
Liver Microsomes ◽  
Cytochrome P450s ◽  
Human Liver Microsomes ◽  
Time Dependent ◽  
Dependent Manner ◽  
Dependent Inhibition ◽  
Drug Inhibition ◽  
Time Dependent Inhibition

The stereoselectivity of the food drug inhibition potential of resveratrol on cytochrome P450s and uridine 5′-diphosphoglucuronosyl transferases was investigated in human liver microsomes. Resveratrol enantiomers showed stereoselective inhibition of CYP2C9, CYP3A, and UGT1A1. The inhibitions of CYP1A2, CYP2B6, and CYP2C19 by resveratrol were stereo-nonselective. The estimated Ki values determined for CYP1A2 were 13.8 and 9.2 μM for trans- and cis-resveratrol, respectively. Trans-resveratrol noncompetitively inhibited CYP3A and UGT1A1 activities with Ki values of 23.8 and 27.4 μM, respectively. Trans-resveratrol inhibited CYP1A2, CYP2C19, CYP2E1, and CYP3A in a time-dependent manner with Ki shift values >2.0, while cis-resveratrol time-dependently inhibited CYP2C19 and CYP2E1. The time-dependent inhibition of trans-resveratrol against CYP3A4, CYP2E1, CYP2C19, and CYP1A2 was elucidated using glutathione as a trapping reagent. This information helped the prediction of food drug interaction potentials between resveratrol and co-administered drugs which are mainly metabolized by UGT1A1, CYP1A2, CYP2C19, CYP2E1, and CYP3A.

scholarly journals Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 371
Author(s):  
Hyung-Ju Seo ◽  
Seung-Bae Ji ◽  
Sin-Eun Kim ◽  
Gyung-Min Lee ◽  
So-Young Park ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Hepatoprotective Activity ◽  
Human Liver Microsomes ◽  
Time Dependent ◽  
Dependent Manner ◽  
Dependent Inhibition ◽  
Night Sweats ◽  
Gomisin A ◽  
Time Dependent Inhibition

Schisandra chinensis has been widely used as a traditional herbal medicine to treat chronic coughs, fatigue, night sweats, and insomnia. Numerous bioactive components including lignans have been identified in this plant. Lignans with a dibenzocyclooctadiene moiety have been known to possess anti-cancer, anti-inflammatory, and hepatoprotective activity. Fragmentary studies have reported the ability of some lignans to modulate some cytochrome P450 (P450) enzymes. Herein, we investigated the drug interaction potential of six dibenzocyclooctadiene lignans (schisandrin, gomisin A, B, C, and N, and wuweizisu C) on nine P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) and six uridine 5′-diphosphoglucuronosyl transferase (UGT) enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) using human liver microsomes. We found that lignans with one or two methylenedioxyphenyl groups inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 activities in a time- and concentration-dependent like their CYP3A inhibition. In comparison, these lignans do not induce time-dependent inhibition of CYP1A2, CYP2A6, and CYP2D6. The time-dependent inhibition of gomisin A against CYP2C8, CYP2C19, and CYP3A4 was also elucidated using glutathione as a trapping reagent of reactive carbene metabolites given that gomisin A strongly inhibits these P450 enzymes in a time-dependent manner. A glutathione conjugate of gomisin A was generated in reactions with human recombinant CYP2C8, CYP2C19, and CYP3A4. This suggests that the time-dependent inhibition of gomisin A against CYP2C8, CYP2C9, and CYP3A4 is due to the production of carbene reactive metabolite. Six of the lignans we tested inhibited the activities of six UGT to a limited extent (IC50 > 15 μM). This information may aid the prediction of possible drug interactions between Schisandra lignans and any co-administered drugs which are mainly metabolized by P450s.

Time dependent inhibition of P450 by phenelzine in human liver microsomes

2018 ◽  
Vol 33 (1) ◽  
pp. S34
Author(s):  
Mandy Xu ◽  
Yu Wang ◽  
Cui Yuan ◽  
Danxi Li ◽  
Stephen Harris
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Time Dependent ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition
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