Inhibitory Mechanisms of Myricetin on Human and Rat Liver Cytochrome P450 Enzymes

Lou, Dan; Bao, Su-su; Li, Yinghui; Lin, Qianmeng; Yang, Su-fen; He, Jiayang

doi:10.1007/s13318-019-00546-y

Cited by 19 publications

(7 citation statements)

References 38 publications

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“…Amodiaquine is metabolized majorly by CYP2C8 with minor contributions from CYP2D6 and CYP3A4 . Myricetin is reported to inhibit the enzymatic activities of CYP3A4 (IC 50 values of 10.7 or 20.3 μM) and CYP2D6 (IC 50 value of 30.2 μM). − Therefore, myricetin showed weak inhibition toward these two CYP isoforms, which suggest that any modulation in the pharmacokinetics of amodiaquine will be unlikely due to the interaction of myricetin with CYP3A4 or CYP2D6. Then, the pharmacokinetic study of amodiaquine was performed in the absence or presence of myricetin in rats.…”

Section: Resultsmentioning

confidence: 99%

“…This CYP-mediated pharmacokinetic interaction may lead to precipitation of adverse effects or therapeutic failure of drugs unless otherwise devoid of any pharmacokinetic interaction, which is very beneficial for safe coadministration. Myricetin is reported to be able to interfere with several CYPs (CYP3A4/CYP2D6/CYP2C9/CYP2B6/CYP1A2) to modulate the pharmacokinetics of several drugs. − However, there is hardly any information available on the CYP2C8 inhibitory potential of myricetin. This CYP2C8 is crucial for drug interaction and unequivocally important for the metabolism of endogenous substances like other key CYPs (CYP2E1, and CYP2J2).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Myricetin on CYP2C8 Inhibition to Assess the Likelihood of Drug Interaction Using In Silico, In Vitro, and In Vivo Approaches

et al. 2022

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Myricetin, a bioflavonoid, is widely used as functional food/complementary medicine and has promising multifaceted pharmacological actions against therapeutically validated anticancer targets. On the other hand, CYP2C8 is not only crucial for alteration in the pharmacokinetics of drugs to cause drug interaction but also unequivocally important for the metabolism of endogenous substances like the formation of epoxyeicosatrienoic acids (EETs), which are considered as signaling molecules against hallmarks of cancer. However, there is hardly any information known to date about the effect of myricetin on CYP2C8 inhibition and, subsequently, the CYP2C8-mediated drug interaction potential of myricetin at the preclinical/clinical level. We aimed here to explore the CYP2C8 inhibitory potential of myricetin using in silico , in vitro , and in vivo investigations. In the in vitro study, myricetin showed a substantial effect on CYP2C8 inhibition in human liver microsomes using CYP2C8-catalyzed amodiaquine- N -deethylation as an index reaction. Considering the Lineweaver–Burk plot, the Dixon plot, and the higher α-value, myricetin is found to be a mixed type of CYP2C8 inhibitor. Moreover, in vitro – in vivo extrapolation data suggest that myricetin is likely to cause drug interaction at the hepatic level. The molecular docking study depicted a strong interaction between myricetin and the active site of the human CYP2C8 enzyme. Moreover, myricetin caused considerable elevation in the oral exposure of amodiaquine as a CYP2C8 substrate via a slowdown of amodiaquine clearance in the rat model. Overall, the potent action of myricetin on CYP2C8 inhibition indicates that there is a need for further exploration to avoid drug interaction-mediated precipitation of obvious adverse effects as well as to optimize anticancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Myricetin on CYP2C8 Inhibition to Assess the Likelihood of Drug Interaction Using In Silico, In Vitro, and In Vivo Approaches

et al. 2022

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“…Therefore, vortioxetine can be determined as a potential liver drug enzyme inhibitor. The mechanism of drug inhibition on CYP450 enzymes can be divided into reversible inhibition and irreversible inhibition ( Lou et al, 2019 ). Reversible mechanisms are divided into competitive inhibition, noncompetitive inhibition, uncompetitive inhibition and mixed inhibition.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory mechanism of vortioxetine on CYP450 enzymes in human and rat liver microsomes

Zhan,

Wang,

et al. 2023

Front. Pharmacol.

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Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on drug-drug interactions (DDI) about vortioxetine. In this paper, the inhibitory effect of vortioxetine on cytochrome P450 (CYP450) and the type of inhibitory mechanism were investigated in human and rat liver microsomes. We set up an in vitro incubation system of 200 μL to measure the metabolism of probe substrates at the present of vortioxetine at 37°C. The concentrations of the metabolites of probe substrates were all measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. It was found no time-dependent inhibition (TDI) of vortioxetine through determination of half-maximal inhibitory concentration (IC50) shift values. The enzymes and metabolites involved in this experiment in human and rats were as follows: CYP3A4/CYP3A (midazolam); CYP2B6/CYP2B (bupropion); CYP2D6/CYP2D (dextromethorphan); CYP2C8/CYP2C-1 (amodiaquine); CYP2C9/CYP2C-2 (losartan); and CYP2C19/CYP2C-3 (mephenytoin). We found that vortioxetine competitively inhibited CYP2C19 and CYP2D6 in human liver microsomes (HLMs) with inhibition constant (Ki) values of 2.17 μM and 9.37 μM, respectively. It was noncompetitive inhibition for CYP3A4 and CYP2C8, and its Ki values were 7.26 μM and 6.96 μM, respectively. For CYP2B6 and CYP2C9, vortioxetine exhibited the mixed inhibition with Ki values were 8.55 μM and 4.17 μM, respectively. In RLMs, the type of vortioxetine inhibition was uncompetitive for CYP3A and CYP2D (Ki = 4.41 and 100.9 μM). The inhibition type was competitive inhibition, including CYP2B and CYP2C-2 (Ki = 2.87 and 0.12 μM). The inhibition types of CYP2C-1 and CYP2C-3 (Ki = 39.91 and 4.23 μM) were mixed inhibition and noncompetitive inhibition, respectively. The study of the above mechanism will provide guidance for the safe clinical use of vortioxetine so that the occurrence of DDI can be avoided.

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“…Studying the inhibitory mechanism of the above three CYP450 isoforms was meaningful. As shown in Table 3 and Figure 5, the IC 50 fold-shift (the ratio of the IC 50 absence of NADPH divided by the IC 50 presence of NADPH) of CYP2B6 was <1, indicating a right shift, while that of CYP2A6 and CYP2D6 was a left shift [55]. The IC 50 fold-shift values were <1.5 [35], which indicated that LKMS might not be a time-dependent inhibitor of CYP2A6, CYP2B6, and CYP2D6.…”

Section: Irreversible Inhibition (Ic 50 Shift)mentioning

confidence: 92%

Inhibitory Mechanisms of Lekethromycin in Dog Liver Cytochrome P450 Enzymes Based on UPLC-MS/MS Cocktail Method

Sun,

Cao,

Qiu

et al. 2023

Molecules

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Lekethromycin (LKMS) is a synthetic macrolide compound derivative intended for use as a veterinary medicine. Since there have been no in vitro studies evaluating its potential for drug–drug interactions related to cytochrome P450 (CYP450) enzymes, the effect of the inhibitory mechanisms of LKMS on CYP450 enzymes is still unclear. Thus, this study aimed to evaluate the inhibitory effects of LKMS on dog CYP450 enzymes. A cocktail approach using ultra-performance liquid chromatography–tandem mass spectrometry was conducted to investigate the inhibitory effect of LKMS on canine CYP450 enzymes. Typical probe substrates of phenacetin, coumarin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and testosterone were used for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4, respectively. This study showed that LKMS might not be a time-dependent inhibitor. LKMS inhibited CYP2A6, CYP2B6, and CYP2D6 via mixed inhibition. LKMS exhibited mixed-type inhibition against the activity of CYP2A6 with an inhibition constant (Ki) value of 135.6 μΜ. LKMS inhibited CYP2B6 in a mixed way, with Ki values of 59.44 μM. A phenotyping study based on an inhibition assay indicated that CYP2D6 contributes to the biotransformation of LKMS. A mixed inhibition of CYP2D6 with Ki values of 64.87 μM was also observed. Given that this study was performed in vitro, further in vivo studies should be conducted to identify the interaction between LKMS and canine CYP450 enzymes to provide data support for the clinical application of LKMS and the avoidance of adverse interactions between other drugs.

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Inhibitory Mechanisms of Myricetin on Human and Rat Liver Cytochrome P450 Enzymes

Cited by 19 publications

References 38 publications

Effect of Myricetin on CYP2C8 Inhibition to Assess the Likelihood of Drug Interaction Using In Silico, In Vitro, and In Vivo Approaches

Effect of Myricetin on CYP2C8 Inhibition to Assess the Likelihood of Drug Interaction Using In Silico, In Vitro, and In Vivo Approaches

Inhibitory mechanism of vortioxetine on CYP450 enzymes in human and rat liver microsomes

Inhibitory Mechanisms of Lekethromycin in Dog Liver Cytochrome P450 Enzymes Based on UPLC-MS/MS Cocktail Method

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