Modulation of <scp>CYP</scp>450 Activities in Patients With Type 2 Diabetes

Gravel, Sophie; Chiasson, Jean‐Louis; Turgeon, Jacques; Grangeon, Alexia; Michaud, Véronique

doi:10.1002/cpt.1496

Cited by 69 publications

(113 citation statements)

References 45 publications

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“…Thus, intending to explore as much DDIs as possible, we chose those six probe drugs for wider coverage: phenacetin (CYP1A2), b u p r o p i o n ( C Y P 2 B 6 ) , t o l b u t a m i d e ( C Y P 2 C 9 ) , dextromethorphan (CYP2D6), midazolam (CYP3A), and chlorzoxazone (CYP2E1). Those similar enzymes also have been detected in other clinical trials (Gravel et al, 2019). We utilized the system we established before, which is more convincing and reliable.…”

Section: Discussionmentioning

confidence: 92%

Cytochrome P450-Based Drug-Drug Interactions of Vonoprazan In Vitro and In Vivo

Wang

et al. 2020

Front. Pharmacol.

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Background: Vonoprazan fumarate is a potassium-competitive acid blocker that was developed as a novel acid-suppressing drug for multiple indications. As a potential alternative to proton-pump inhibitors, the determination of the drug-drug interactions is vital for further applications. Probe drug cocktails are a type of rapid, economical, and efficient approach for evaluating cytochrome P450 enzyme activities. Since vonoprazan is metabolized partly by cytochrome P450, cocktails were used to study CYP-based drugdrug interactions. Methods: This study was conducted both in vitro and in vivo. In the in vitro study of rat liver microsomes, ultra-performance liquid chromatography coupled to tandem mass spectrometry was utilized to assess the reversible inhibition of cytochrome P450 by vonoprazan by determining the concentration of probe drugs (phenacetin, bupropion, tolbutamide, dextromethorphan, midazolam, chlorzoxazone). The differences in the levels of probe drugs between the rat groups with or without vonoprazan administration were also tested in the rats. Results: In vitro analysis revealed that the IC 50 values of midazolam, tolbutamide, dextromethorphan, and bupropion in rat microsomes were 22.48, 18.34, 3.62, and 3.68 mM, respectively, while chlorzoxazone and phenacetin displayed no inhibition. In vivo analysis revealed that midazolam, bupropion, dextromethorphan, and tolbutamide showed significant (P < 0.05) differences in distinct pharmacokinetic parameters after vonoprazan administration, while those of chlorzoxazone and phenacetin were not significantly different. Conclusion: The in vitro and in vivo results indicated that vonoprazan can inhibit CYP3A4, CYP2C9, CYP2D6, and CYP2B6, suggesting that the coadministration of vonoprazan with cytochrome P450 substrates should be performed cautiously in clinical settings.

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Section: Discussionmentioning

confidence: 92%

Cytochrome P450-Based Drug-Drug Interactions of Vonoprazan In Vitro and In Vivo

Wang

et al. 2020

Front. Pharmacol.

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“…Although these data are concordant, the role of inflammation in such CYP downregulation in diabetes has never been investigated. Recently, a prospective study using a cocktail of probe drugs showed a decrease of approximately 38, 46, and 45% of the mean metabolic activity for CYP3A, 2C19, and 2B6, respectively, in 38 patients with type 2 diabetes relative to 35 controls ( Gravel, Chiasson, Turgeon, Grangeon, & Michaud, 2019 ). Considering all diabetic and non-diabetic subjects, the IL-6 concentration significantly negatively correlated with the activities of CYP2B6, 2C19, and 3A in univariate analysis.…”

Section: Pharmacological Consequences Of Inflammation-induced Metabolmentioning

confidence: 99%

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

Stanke‐Labesque

Gautier-Veyret

Chhun

et al. 2020

Pharmacology & Therapeutics

131

147

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Inflammation is an evolutionary process that allows survival against acute infection or injury. Inflammation is also a pathophysiological condition shared by numerous chronic diseases. In addition, inflammation modulates important drug-metabolizing enzymes and transporters (DMETs), thus contributing to intra- and interindividual variability of drug exposure. A better knowledge of the impact of inflammation on drug metabolism and its related clinical consequences would help to personalize drug treatment. Here, we summarize the kinetics of inflammatory mediators and the underlying transcriptional and post-transcriptional mechanisms by which they contribute to the inhibition of important DMETs. We also present an updated overview of the effect of inflammation on the pharmacokinetic parameters of most of the drugs that are DMET substrates, for which therapeutic drug monitoring is recommended. Furthermore, we provide opinions on how to integrate the inflammatory status into pharmacogenetics, therapeutic drug monitoring, and population pharmacokinetic strategies to improve the personalization of drug treatment for each patient.

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“…As shown in recent studies, chronic inflammation was associated with significantly reduced CYP2C19 activity by 46% in patients with type 2 diabetes. 31 In the OPTIMUS study, activity was reported to be reduced by 60% and patients with type 2 diabetes remained poor responders although maintenance doses of clopidogrel were doubled. 32 Although gender-specific CYP2C19 gene expression has been observed in mice (higher in men than women in the liver and kidneys), this remains controversial in human studies.…”

Section: Other Factors That Can Influence Cyp2c19 Activitymentioning

confidence: 99%