In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data

Arora, Sumit; Taneja, Isha; Challagundla, Muralikrishna; Raju, K. Kanaka; Singh, Sheelendra Pratap; Wahajuddin, Muhammad

doi:10.1016/j.toxlet.2015.08.202

Cited by 50 publications

(37 citation statements)

References 33 publications

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“…The two isoflavones, formononetin and biochanin A, significantly inhibit CYP 1A2 in both human and rat liver microsomes in vitro. Formononetin also significantly inhibits CYP 2D6, and biochanin A also inhibits human CYP 2C9 [147]. CYP 1B1 is inhibited by flavone [148], chrysin [148], apigenin [148], genistein [148], luteolin [149], quercetein [149], galangin [149], myricetin [150], and many others.…”

Section: Challenges In Flavonoids In Cancer Chemoprevention Developmentmentioning

confidence: 99%

Cancer chemoprevention through dietary flavonoids: what’s limiting?

2017

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Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their effective use, including (1) the isolation and purification of flavonoids from their natural resources; (2) demonstration of the effects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and (3) numerous pharmacokinetic challenges (e.g., bioavailability, drug–drug interactions, and metabolic instability). Currently, numerous approaches are being used to surmount some of these challenges, thereby increasing the likelihood of flavonoids being used as chemo-preventive drugs in the clinic. In this review, we summarize the most important challenges and efforts that are being made to surmount these challenges.

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Section: Challenges In Flavonoids In Cancer Chemoprevention Developmentmentioning

confidence: 99%

Cancer chemoprevention through dietary flavonoids: what’s limiting?

2017

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“…Effect of IS01957 on inhibition of CYP2C9 was executed in the concentration range of 0–25 μM using substrate concentration of 5 μM which was based on the preliminary results to determine Km which matched with the previous literature (Arora et al, ; Bhateria et al, ). Sulfaphenazole was used as positive control to elucidate the validity of the probe reactions and IC 50 was found to be 0.41 μM which is in good agreement with the reported results (Arora et al, ; Bhateria et al, ). IS01957 displayed the IC 50 of 18.14 μM for the impediment of CYP2C9 mediated marker reaction.…”

Section: Resultsmentioning

confidence: 92%

“…The study was performed using sulfaphenazole as a standard inhibitor. Rate of metabolite formation was calculated where reaction mixture without inhibitor was considered as control and IC 50 was determined using GraphPad Prism software (Arora et al, ; Bhateria, Ramakrishna, Puttrevu, Saxena, & Bhatta, ).…”

Section: Methodsmentioning

confidence: 99%

“…Estimation of the inhibitory potential of CYP2C9 by IS01957 in HLM was an essential part of these investigations and hence taken up using index reaction of diclofenac 4-hydroxylation where diclofenac was used as a substrate for this CYP2C9 mediated marker reactions as per USFDA guidelines (Drug development and drug interactions, USFDA). Effect of IS01957 on inhibition of CYP2C9 was executed in the concentration range of 0-25 μM using substrate concentration of 5 μM which was based on the preliminary results to determine Km which matched with the previous literature (Arora et al, 2015;Bhateria et al, 2016).…”

Section: Possible Role Of Is01957 For Bioenhancementmentioning

confidence: 96%

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Effect of IS01957, a para‐coumaric acid derivative on pharmacokinetic modulation of diclofenac through oral route for augmented efficacy

Sharma

Gour

Bhatt

et al. 2019

Drug Development Research

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Diclofenac is one of the world's largest selling nonsteroidal anti‐inflammatory drugs. The major concerns related to oral diclofenac therapy are gastrointestinal and cardiovascular side effects for which explicitly emphasis has been given to use it at lowest effective dose for the shortest duration. On the other hand, IS01957 has been designed under the purview of anti‐inflammatory drug and bioavailability enhancer. IS01957 have dual action on inflammation and nociception with acceptable safety profile. In the quest for a suitable combination with improved therapeutic efficacy and better tolerability, pharmacodynamic and pharmacokinetic interaction studies were performed for diclofenac with or without IS01957 in mice model. Results showed that IS01957 enhanced both anti‐inflammatory effect and plasma concentration of diclofenac upon concomitant oral administration. These interesting results steered to enumerate the possible role of IS01957 towards diclofenac pharmacokinetics through a panel of mechanistic investigations: (a) BCRP dependent ATPase activity was markedly interfered by IS01957; (b) IS01957 increased the intestinal permeability of diclofenac in the single pass in‐situ perfusion model; (c) IS01957 inhibited the CYP2C9 catalyzed diclofenac 4‐hydroxylation in human liver microsomes. Immunoblotting results suggest that diclofenac action was improved significantly in the presence of IS01957 involving MAPK pathways. Finally acute gastric damage study showed that IS01957 in combination with diclofenac was better to improve the desired PGE2 level as compare to alone. In nutshell, IS01957 have potential to augment the efficacy of diclofenac through pharmacokinetic modulation. Further investigations are required for dose reduction of diclofenac to combat its liabilities before going into clinical setting.

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“…15) product inhibited CYP1A2 and CYP2C9. The isoflavone-based product contained isoflavones derived from soybean and red clover, such as genistein and biochanin A, which reportedly inhibit CYP1A2 [18, 19]. In contrast, few reports are available on P450 inhibition by vitamins in vitamin-based products, although lipid-soluble vitamins, such as vitamin A and vitamin D, have been reported to induce CYPs [20, 21].…”

Section: Discussionmentioning

confidence: 99%

Effect of health foods on cytochrome P450-mediated drug metabolism

Sasaki

Sato

Kumagai

et al. 2017

J Pharm Health Care Sci

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BackgroundHealth foods have been widely sold and consumed in Japan. There has been an increase in reports of adverse effects in association with the expanding health food market. While health food-drug interactions are a particular concern from the viewpoint of safe and effective use of health foods, information regarding such interactions is limited owing to the lack of established methods to assess the effects of health food products on drug metabolism. We therefore developed cells that mimicked the activities of cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4, which strongly contribute to drug metabolism in human hepatocytes, and established a system to assess the inhibitory activity of health foods toward P450-mediated metabolism.MethodsWe simultaneously infected HepG2 cells with five P450-expressing adenoviruses (Ad-CYP1A2, Ad-CYP2C9, Ad-CYP2C19, Ad-CYP2D6, and Ad-CYP3A4) to mimic the activity levels of these P450s in human hepatocytes, and named them Ad-P450 cells. The activity levels of P450s in Ad-P450 cells and human hepatocytes were calculated via simultaneous liquid chromatography/tandem mass spectrometry analysis utilizing a P450 substrate cocktail.ResultsWe established Ad-P450 cells mimicking the activity levels of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human hepatocytes. We determined the Km values of P450 substrates and IC50 values of P450 inhibitors in Ad-P450 cells. These values were approximately equivalent to those obtained in previous studies. We investigated the inhibitory effects of 172 health foods that were recently in circulation in Japan on P450-mediated metabolism using Ad-P450 cells. Of the 172 health foods, five products (two products having dietary effects, one turmeric-based product, one collagen-based product, and one propolis-containing product) simultaneously inhibited the five P450s by more than 50%. Another 29 products were also confirmed to inhibit one or more P450s.ConclusionsWe established a comprehensive assessment system to elucidate the effects of health foods on P450-mediated metabolism and identified the inhibitory activity of 34 of 172 health foods toward the drug-metabolizing P450s. Our results may provide useful information to predict health food-drug interactions.

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In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data

Cited by 50 publications

References 33 publications

Cancer chemoprevention through dietary flavonoids: what’s limiting?

Cancer chemoprevention through dietary flavonoids: what’s limiting?

Effect of IS01957, a para‐coumaric acid derivative on pharmacokinetic modulation of diclofenac through oral route for augmented efficacy

Effect of health foods on cytochrome P450-mediated drug metabolism

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