scholarly journals Predictive In Vitro-In Vivo Extrapolation for Time Dependent Inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 Using Pooled Human Hepatocytes, Human Liver Microsomes, and a Simple Mechanistic Static Model

2021 ◽  
pp. DMD-AR-2021-000718
Author(s):  
Diane Ramsden ◽  
Elke S. Perloff ◽  
Andrea Whitcher-Johnstone ◽  
Thuy Ho ◽  
Reena Patel ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Static Model ◽  
Human Hepatocytes ◽  
Time Dependent ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition ◽  
In Vivo Extrapolation

scholarly journals Reversible, Time-Dependent Inhibition of CYP3A-Mediated Metabolism of Midazolam and Tacrolimus by Telaprevir in Human Liver Microsomes

2015 ◽  
Vol 18 (1) ◽  
pp. 101 ◽  
Author(s):  
Brian Chapron ◽  
Linda Risler ◽  
Brian Phillips ◽  
Carol Collins ◽  
Kenneth Thummel ◽  
...  
Keyword(s):  
Human Liver ◽  
Competitive Inhibition ◽  
Human Subjects ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Time Dependent ◽  
Oral Midazolam ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition

Purpose  Telaprevir inhibits CYP3A resulting in drug-drug interactions (DDI) of unprecedented magnitude. We investigated the mechanisms by which telaprevir inhibits the oxidation of midazolam and tacrolimus in human liver microsomes (HLM). Methods  We performed a static mechanistic DDI prediction to evaluate whether previously reported competitive inhibition of CYP3A by telaprevir and its diastereomeric metabolite ― VRT-127394 is sufficient to explain the remarkable reduction in oral clearance observed with oral midazolam and tacrolimus. To further explore the inhibitory mechanisms of telaprevir, we assessed whether telaprevir-mediated inhibition of the oxidation of midazolam and tacrolimus is time-dependent in human liver microsomes, and whether any observed time-dependency was irreversible or reversible in nature. Results  The competitive inhibition model failed to account for the magnitude of telaprevir interactions in human subjects. In comparing HLM incubations with and without a prior 30-min exposure to telaprevir, a respective 4- and 11-fold reduction in IC50 was observed with midazolam and tacrolimus as substrates.  This time-dependent inhibition was shown to be NADPH-dependent. Upon dilution of microsomes following pre-incubation with telaprevir, time-dependent inhibition of midazolam metabolism was completely reversed, whereas partial reversal occurred with tacrolimus. Conclusions  The interaction between telaprevir and midazolam or tacrolimus involves both competitive and time-dependent inhibition. The time-dependent component is not explained by irreversible inactivation of CYP3A. Formation of potent inhibitory metabolites may contribute to the remarkable in vivo inhibitory potency of telaprevir. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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 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 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.

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