Flavonoids Diosmetin and Hesperetin are Potent Inhibitors of Cytochrome P450 2C9-mediated Drug Metabolism in vitro

Quintieri, Luigi; Bortolozzo, Sara; Stragliotto, Stefano; Moro, Stefano; Pavanetto, Martina; Nassi, Alberto; Palatini, Pietro; Floreani, Maura

doi:10.2133/dmpk.dmpk-10-rg-044

Cited by 37 publications

(20 citation statements)

References 45 publications

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“…A number of clinical trials have been conducted using large doses of flavonoids for disease prevention, and there were no serious side effects observed in these studies (19). However, it has been confirmed that several flavonoids are potent inhibitors of CYP2C-mediated drug metabolism (20,21) and thus possess the potential to alter the efficacy of some prescribed drugs (22). Although concomitant administration of high flavonoid-containing substances with therapeutic agents carries the risks of unwanted interactions, these plant-derived compounds may also markedly improve the bioavailability of some orally administered drugs.…”

Section: Introductionmentioning

confidence: 99%

Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship

Wang¹,

Pao²,

Hsiong³

et al. 2014

AAPS J

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Abstract. This study aims to improve the drug oral bioavailability by co-administration with flavonoid inhibitors of the CYP2C isozyme and to establish qualitative and quantitative (QSAR) structure-activity relationships (SAR) between flavonoids and CYP2C. A total of 40 naturally occurring flavonoids were screened in vitro for CYP2C inhibition. Enzyme activity was determined by measuring conversion of tolbutamide to 4-hydroxytolbutamide by rat liver microsomes. The percent inhibition and IC 50 of each flavonoid were calculated and used to develop SAR and QSAR. The most effective flavonoid was orally co-administered in vivo with a cholesterol-reducing drug, fluvastatin, which is normally metabolized by CYP2C. The most potent CYP2C inhibitor identified in vitro was tamarixetin (IC 50 =1.4 μM). This flavonoid enhanced the oral bioavailability of fluvastatin in vivo, producing a >2-fold increase in the area under the concentration-time curve and in the peak plasma concentration. SAR analysis indicated that the presence of a 2,3-double bond in the C ring, hydroxylation at positions 5, 6, and 7, and glycosylation had important effects on flavonoid-CYP2C interactions. These findings should prove useful for predicting the inhibition of CYP2C activity by other untested flavonoid-like compounds. In the present study, tamarixetin significantly inhibited CYP2C activity in vitro and in vivo. Thus, the use of tamarixetin could improve the therapeutic efficacy of drugs with low bioavailability.

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Section: Introductionmentioning

confidence: 99%

Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship

Wang¹,

Pao²,

Hsiong³

et al. 2014

AAPS J

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show abstract

“…Some research has demonstrated the ability of hesperidin or its metabolites to inhibit some hepatic isoenzymes of the cytochrome P-450 [42,43]. Such as cisplatin is a drug which has no known interactions with cytochrome P450 enzymes [44][45][46], it is supposed that hesperidin does not act at the hepatic level, under these experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Hesperidin Reduces Cisplatin-Induced DNA Damage in Bone Marrow Cells of Mice

Passos¹,

Santana²,

Mota³

et al. 2017

JPP

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Hesperidin is a bioflavonoid abundantly found in citrus fruits and displays chemoprotective effects against DNA (deoxyribonucleic acid) damage, however there are few reports about hesperidin effects against cisplatin-DNA damage induction. The aim of this work was to evaluate hesperidin antimutagenicity against cisplatin-DNA damage.(1) The antimutagenicity of hesperidin was assayed by bone marrow of mice in vivo using the micronucleus test. Hesperidin pre-treatment protocol reduced the frequency of MNPCE (micronucleated polychromatic erythrocytes) and the dose of 100 mg·kg , respectively. From the study, it can be concluded that hesperidin was able to promote the reduction of micronuclei frequency and DNA damage induced by cisplatin. Hesperidin is a powerful antioxidant compound and its chemoprotective effects on DNA may occur due to its association with the antioxidant cell system which is responsible for eliminate free radicals generated by chemical harmful to DNA.

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“…[16][17][18] However, the effects of HET and NGR on UGT activity have not been fully characterized. Understanding the effects of HET and NGR on UGT activities is important to ensure their safe administration and development new co-administration therapies with both drugs.…”

Section: )mentioning

confidence: 99%

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Liú

Xie

et al. 2016

Biological & Pharmaceutical Bulletin

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Hesperetin (HET) and naringenin (NGR) are flavanones found in citrus (oranges and grapefruit) andAurantii Fructus Immaturus. The present study aims to investigate the inhibition potential of HET and NGR derivatives towards one of the most important phase II drug-metabolizing enzymes-uridine diphosphate (UDP)-glucuronosyltransferases (UGTs). We used trifluoperazine as a probe substrate to test UGT1A4 activity, and recombinant UGT-catalyzed 4-methylumbelliferone glucuronidation was used as a probe reaction for other UGT isoforms. Data show that HET and NGR displayed broad-spectrum inhibition against human UGTs. Besides, HET exhibited strong inhibitory effects on UGT1A1, 1A3 and 1A9 (both IC 50 and K i values lower than 10 µM), and the inhibitory effects of NGR against three major UGTs, including UGT1A1, 1A3 and 2B7. In a combination of inhibition parameters (K i ) and in vivo concentration of HET and NGR, the potential in vivo inhibition magnitude was predicted. Based on the reported maximum plasma concentration of HET and NGR in vivo, these findings indicate the potential herb-drug interactions (HDI) between HET or NGR and the drugs mainly undergoing UGT1A3 or UGT2B7 catalyzed metabolic elimination. Considering the variety of citrus that contains HET and NGR, so caution should be applied when taking drugs that utilize UGTs for metabolism and clearance with citrus fruits. Key words herb-drug interaction; hesperetin; naringenin; uridine diphosphate (UDP)-glucuronosyltransferaseHesperetin (HET; 4′-methoxy-3′,5,7-trihydroxyflavanone) and naringenin (NGR; 4,5,7-trihydroxyflavanone), aglycones of the flavanone glycoside hesperidin (chiefly in oranges) and naringin (grapefruits) are also used as dietary flavonoids. 1)Moreover, flavanones are bioactive components of Aurantii Fructus Immaturus, which is reported to be used in traditional Chinese medicine.2) Several animal studies have been performed to document pharmacokinetics of HET and NGR. 3,4) The role of HET and NGR in the treatment of disease has received considerable attention, and it is reported to have antioxidant, anti-inflammatory, anti-hypertensive, anti-atherogenic, anti-diabetic, antiviral, and neuroprotective activities. 5-8)Thus, HET and NGR have multiple uses and pharmacokinetic studies of both compounds may elucidate information about efficacy and safety. Chemical structures of HET and NGR appear in Fig. 1.Herb-drug interaction (HDI) strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons.9) CYP450 and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) are two enzymes responsible for oxidative phase I and conjugative phase II reactions, respectively. 10) In the past decades, the CYP450 inhibition by HET and NGR has been widely studied, the effects of HET and NGR on UGTs activity have not been fully characterized. Moreover, a large number of different UGTs that exhibit a wide range of substrates are...

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Flavonoids Diosmetin and Hesperetin are Potent Inhibitors of Cytochrome P450 2C9-mediated Drug Metabolism in vitro

Cited by 37 publications

References 45 publications

Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship

Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship

Hesperidin Reduces Cisplatin-Induced DNA Damage in Bone Marrow Cells of Mice

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

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