Tertiary oxidation of deoxycholate is predictive of CYP3A activity in dogs

2021 ◽  
pp. DMD-AR-2021-000385
Author(s):  
Wushuang Zeng ◽  
Lanlan Gui ◽  
Xianwen Tan ◽  
Pingping Zhu ◽  
Yiting Hu ◽  
...  
Keyword(s):  
Cyp3a Activity

Use of 4β‐Hydroxycholesterol Plasma Concentrations as an Endogenous Biomarker of CYP3A Activity: Clinical Validation in Individuals With Type 2 Diabetes

2019 ◽  
Vol 106 (4) ◽  
pp. 831-840 ◽  
Author(s):  
Sophie Gravel ◽  
Jean‐Louis Chiasson ◽  
Fleur Gaudette ◽  
Jacques Turgeon ◽  
Veronique Michaud
Keyword(s):  
Type 2 Diabetes ◽  
Plasma Concentrations ◽  
Clinical Validation ◽  
Cyp3a Activity

CYP3A activity: towards dose adaptation to the individual

2016 ◽  
Vol 12 (5) ◽  
pp. 479-497 ◽  
Author(s):  
Nicolas Hohmann ◽  
Walter E. Haefeli ◽  
Gerd Mikus
Keyword(s):  
Cyp3a Activity ◽  
Dose Adaptation ◽  
The Individual

In vitro Measurement and In vivo Prediction of Time-Dependent Inhibitory Effects of Three Tyrosine Kinase Inhibitors on CYP3A Activity

2021 ◽  
Vol 22 ◽  
Author(s):  
Liyan Wang ◽  
Tingting Zhao ◽  
Yunxiang Wang ◽  
Banglian Hu ◽  
Jianfei Tao ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Cyp3a Activity ◽  
Drug Drug Interaction ◽  
Inhibitory Potential

Background: Imatinib, sunitinib, and gefitinib are the three most common tyrosine kinase inhibitors (TKIs). However, their quantitative drug-drug interaction potentials In vivo and the relationship between their structure and inhibitory activity remain unknown. Objective: This study aimed to investigate the potential drug-drug interaction risk of three TKIs based on CYP3A. Methods: 6β-Hydroxylated testosterone formation was selected to probe the CYP3A activity in human liver microsomes. Molecular docking simulation was performed to explore the potential structural alerts. Results: Imatinib exhibited the strongest inhibitory effect towards CYP3A, while the inhibitory potential of gefitinib and sunitinib were comparable to each other but weaker than imatinib. IC50 shift assays demonstrated that the inhibitory potential of all three TKIs was significantly increased after a 30-min preincubation with NADPH. The KI and Kinact values of imatinib, sunitinib, and gefitinib were 3.75 μM and 0.055 min–1, 1.96 μM and 0.037 min–1, and 9.94 μM and 0.031 min–1, respectively. IVIVE results showed that there was a 1.3- to 43.1-fold increase in the AUC of CYP3A-metabolizing drugs in the presence of the TKIs. Conclusion: All three TKIs exhibited a typical irreversible inhibitory effect towards CYP3A. The presence of more N-heterocycles and the resulting better binding confirmation of imatinib may have been responsible for its stronger inhibitory effect than sunitinib and gefitinib. Therefore, caution should be taken when CYP3A-metabolizing drugs are co-administrated with imatinib, sunitinib, or gefitinib.

Influence of Hepatic and Intestinal Cytochrome P4503A Activity on the Acute Disposition and Effects of Oral Transmucosal Fentanyl Citrate

2004 ◽  
Vol 101 (3) ◽  
pp. 729-737 ◽  
Author(s):  
Evan D. Kharasch ◽  
Dale Whittington ◽  
Christine Hoffer
Keyword(s):  
Grapefruit Juice ◽  
Pupil Diameter ◽  
Area Under The Curve ◽  
Clinical Effects ◽  
Cyp3a Activity ◽  
Fentanyl Citrate ◽  
Oral Transmucosal Fentanyl Citrate ◽  
First Pass Metabolism ◽  
First Pass ◽  
Pass Metabolism

Background Oral transmucosal fentanyl citrate (OTF) was developed to provide rapid analgesia and is specifically approved for treating breakthrough cancer pain. Fentanyl in OTF is absorbed across the oral mucosa, but a considerable portion is swallowed and absorbed enterally. Fentanyl metabolism is catalyzed by cytochrome P4503A4 (CYP3A). The role of intestinal or hepatic first-pass metabolism and CYP3A activity in OTF disposition is unknown. This investigation examined the influence of hepatic and intestinal CYP3A activity on the disposition and clinical effects of OTF. Methods Healthy volunteers (n = 12) were studied in an Institutional Review Board-approved, randomized, balanced, four-way crossover. They received OTF (10 microg/kg) after hepatic/intestinal CYP3A induction by rifampin, hepatic/intestinal CYP3A inhibition by troleandomycin, selective intestinal CYP3A inhibition by grapefruit juice, or nothing (control). Plasma fentanyl and norfentanyl concentrations were determined by mass spectrometry. Fentanyl effects were measured by dark-adapted pupil diameter and subjective self-assessments using visual analog scales. Results : Peak plasma fentanyl concentrations, time to peak, and maximum pupil diameter change from baseline were unchanged after rifampin, troleandomycin, and grapefruit juice. Fentanyl elimination, however, was significantly affected by CYP3A alterations. After control, rifampin, troleandomycin and grapefruit juice, respectively, area under the curve of plasma fentanyl versus time was 5.9 +/- 3.7, 2.2 +/- 0.8,* 10.4 +/- 8.9,* and 5.8 +/- 3.3 h x ng/ml; norfentanyl/fentanyl plasma area under the curve ratios were 0.92 +/- 0.63, 3.2 +/- 1.8,* 0.08 +/- 0.14,* and 0.67 +/- 0.33 (*P < 0.05 versus control). Discussion Peak fentanyl concentrations and clinical effects after OTF were minimally affected by altering both intestinal and hepatic CYP3A activity, whereas fentanyl metabolism, elimination, and duration of effects were significantly affected; selective intestinal CYP3A inhibition had minimal effects. This suggests that first-pass metabolism minimally influences OTF bioavailability. When treating breakthrough pain, with careful attention to maximal mucosal absorption and minimal swallowing, CYP3A variability and drug interactions are unlikely to affect the onset or magnitude of OTF analgesia; however, duration may be affected.

scholarly journals Studies on CYP3A activity during the menstrual cycle as measured by urinary 6β‐hydroxycortisol/cortisol

2021 ◽  
Vol 9 (6) ◽  
Author(s):  
Helena Bergström ◽  
Anna Lindahl ◽  
Anna Warnqvist ◽  
Ulf Diczfalusy ◽  
Lena Ekström ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Cyp3a Activity

scholarly journals Comparison of urinary 6-β-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity

1992 ◽  
Vol 52 (3) ◽  
pp. 265-273 ◽  
Author(s):  
Paul B Watkins ◽  
D Kim Turgeon ◽  
Paul Saenger ◽  
Kenneth S Lown ◽  
Joseph C Kolars ◽  
...  
Keyword(s):  
Breath Test ◽  
Cyp3a Activity ◽  
Erythromycin Breath Test

Effect of buprenorphine on CYP3A activity in rat and human liver microsomes

Life Sciences ◽  
2000 ◽  
Vol 66 (14) ◽  
pp. 1293-1298 ◽  
Author(s):  
Rami B. Ibrahim ◽  
Jacquelyn G. Wilson ◽  
Mary E. Thorsby ◽  
David J. Edwards
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Cyp3a Activity

scholarly journals Which cytochrome P450 metabolizes phenazepam? Step by step in silico, in vitro, and in vivo studies

2018 ◽  
Vol 33 (2) ◽  
pp. 65-73 ◽  
Author(s):  
Dmitriy V. Ivashchenko ◽  
Anastasia V. Rudik ◽  
Andrey A. Poloznikov ◽  
Sergey V. Nikulin ◽  
Valeriy V. Smirnov ◽  
...  
Keyword(s):  
Cell Culture ◽  
Cytochrome P450 ◽  
In Silico ◽  
In Vivo Studies ◽  
Cyp3a Activity ◽  
Cell Culture Study ◽  
Study Results ◽  
Three Stages

Abstract Background: Phenazepam (bromdihydrochlorphenylbenzodiazepine) is the original Russian benzodiazepine tranquilizer belonging to 1,4-benzodiazepines. There is still limited knowledge about phenazepam’s metabolic liver pathways and other pharmacokinetic features. Methods: To determine phenazepam’s metabolic pathways, the study was divided into three stages: in silico modeling, in vitro experiment (cell culture study), and in vivo confirmation. In silico modeling was performed on the specialized software PASS and GUSAR to evaluate phenazepam molecule affinity to different cytochromes. The in vitro study was performed using a hepatocytes’ cell culture, cultivated in a microbioreactor to produce cytochrome P450 isoenzymes. The culture medium contained specific cytochrome P450 isoforms inhibitors and substrates (for CYP2C9, CYP3A4, CYP2C19, and CYP2B6) to determine the cytochrome that was responsible for phenazepam’s metabolism. We also measured CYP3A activity using the 6-betahydroxycortisol/cortisol ratio in patients. Results: According to in silico and in vitro analysis results, the most probable metabolizer of phenazepam is CYP3A4. By the in vivo study results, CYP3A activity decreased sufficiently (from 3.8 [95% CI: 2.94–4.65] to 2.79 [95% CI: 2.02–3.55], p=0.017) between the start and finish of treatment in patients who were prescribed just phenazepam. Conclusions: Experimental in silico and in vivo studies confirmed that the original Russian benzodiazepine phenazepam was the substrate of CYP3A4 isoenzyme.

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