Asset Details
Do you wish to reserve the book?
In Vitro and In Vivo Evaluations of Cytochrome P450 1A2 Interactions with Duloxetine
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
In Vitro and In Vivo Evaluations of Cytochrome P450 1A2 Interactions with Duloxetine
Do you wish to request the book?
In Vitro and In Vivo Evaluations of Cytochrome P450 1A2 Interactions with Duloxetine
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
In Vitro and In Vivo Evaluations of Cytochrome P450 1A2 Interactions with Duloxetine
2008
Overview
Objective:
To determine whether duloxetine is a substrate, inhibitor or inducer of cytochrome P450 (CYP) 1A2 enzyme, using
in vitro
and
in vivo
studies in humans.
Methods:
Human liver microsomes or cells with expressed CYP enzymes and specific CYP inhibitors were used to identify which CYP enzymes catalyse the initial oxidation steps in the metabolism of duloxetine. The potential of duloxetine to inhibit CYP1A2 activity was determined using incubations with human liver microsomes and phenacetin, the CYP1A2 substrate. The potential for duloxetine to induce CYP1A2 activity was determined using human primary hepatocytes treated with duloxetine for 72 hours. Studies in humans were conducted using fluvoxamine, a potent CYP1A2 inhibitor, and theophylline, a CYP1A2 substrate, as probes. The subjects were healthy men and women aged 18–65 years. Single-dose duloxetine was administered either intravenously as a 10-mg infusion over 30 minutes or orally as a 60-mg dose in the presence or absence of steady-state fluvoxamine (100 mg orally once daily). Single-dose theophylline was given as 30-minute intravenous infusions of aminophylline 250 mg in the presence or absence of steady-state duloxetine (60 mg orally twice daily). Plasma concentrations of duloxetine, its metabolites and theophylline were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods and evaluated using mixed-effects ANOVA. Safety measurements included vital signs, clinical laboratory tests, a physical examination, ECG readings and adverse event reports.
Results:
The
in vitro
results indicated that duloxetine is metabolized by CYP1A2; however, duloxetine was predicted not to be an inhibitor or inducer of CYP1A2 in humans. Following oral administration in the presence of fluvoxamine, the duloxetine area under the plasma concentration-time curve from time zero to infinity (AUC
∞
) and the maximum plasma drug concentration (C
max
) significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In the presence of fluvoxamine, the oral bioavailability of duloxetine increased from 42.8% to 81.9%. In the presence of duloxetine, the theophylline AUC
∞
and C
max
increased by only 13% (90% CI 7, 18) and 7% (90% CI 2,14), respectively. Coadministration of duloxetine with fluvoxamine or theophylline did not result in any clinically important safety concerns, and these combinations were generally well tolerated.
Conclusion:
Duloxetine is metabolized primarily by CYP1A2; therefore, coadministration of duloxetine with potent CYP1A2 inhibitors should be avoided. Duloxetine does not seem to be a clinically significant inhibitor or inducer of CYP1A2; therefore, dose adjustment of CYP1A2 substrates may not be necessary when they are coadministered with duloxetine.
Publisher
Springer International Publishing,Adis international,Wolters Kluwer Health, Inc,Springer Nature B.V
Subject
/ Adult
/ Biological and medical sciences
/ Cytochrome P-450 CYP1A2 - drug effects
/ Cytochrome P-450 CYP1A2 - metabolism
/ Female
/ Humans
/ Male
/ Medicine
/ Microsomes, Liver - metabolism
/ Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
/ Pharmacology. Drug treatments
/ Serotonin Uptake Inhibitors - adverse effects
/ Serotonin Uptake Inhibitors - pharmacokinetics
/ Serotonin Uptake Inhibitors - pharmacology
/ Smoking
/ Theophylline - pharmacokinetics
/ Thiophenes - adverse effects
