In vitro study on the effect of peucedanol on the activity of cytochrome P450 enzymes

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

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The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: An in vitro study

Pharmacological Research ◽

10.1016/j.phrs.2012.10.009 ◽

2013 ◽

Vol 67 (1) ◽

pp. 53-59 ◽

Cited By ~ 19

Author(s):

Anna Haduch ◽

Ewa Bromek ◽

Anna Sadakierska-Chudy ◽

Jacek Wójcikowski ◽

Władysława A. Daniel

Keyword(s):

Cytochrome P450 ◽

In Vitro Study ◽

Vitro Study ◽

The Brain

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In vitro study of modulatory effects of extracts of Strobilanthes crispus on human cDNA-expressed cytochrome P450 2A6 (CYP2A6)

Drug Metabolism and Pharmacokinetics ◽

10.1016/j.dmpk.2016.10.268 ◽

2017 ◽

Vol 32 (1) ◽

pp. S67

Author(s):

Pan Yan ◽

Rhun Yian Koh ◽

Chin Eng Ong ◽

Jin Yu Chieng

Keyword(s):

Cytochrome P450 ◽

In Vitro Study ◽

Vitro Study ◽

Human Cdna ◽

Strobilanthes Crispus ◽

Cytochrome P450 2A6

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Cytochrome P450 enzymes: a review on drug metabolizing enzyme inhibition studies in drug discovery and development

Bioanalysis ◽

10.4155/bio-2021-0132 ◽

2021 ◽

Vol 13 (17) ◽

pp. 1355-1378

Author(s):

Siva Nageswara Rao Gajula ◽

Megha Sajakumar Pillai ◽

Gananadhamu Samanthula ◽

Rajesh Sonti

Keyword(s):

Cytochrome P450 ◽

Drug Discovery ◽

Enzyme Inhibition ◽

In Vitro Study ◽

Cytochrome P450 Enzymes ◽

Drug Discovery And Development ◽

Drug Candidates ◽

Cyp Enzymes ◽

Cyp Inhibition

Assessment of drug candidate's potential to inhibit cytochrome P450 (CYP) enzymes remains crucial in pharmaceutical drug discovery and development. Both direct and time-dependent inhibition of drug metabolizing CYP enzymes by the concomitant administered drug is the leading cause of drug–drug interactions (DDIs), resulting in the increased toxicity of the victim drug. In this context, pharmaceutical companies have grown increasingly diligent in limiting CYP inhibition liabilities of drug candidates in the early stages and examining risk assessments throughout the drug development process. This review discusses different strategies and decision-making processes for assessing the drug–drug interaction risks by enzyme inhibition and lays particular emphasis on in vitro study designs and interpretation of CYP inhibition data in a stage-appropriate context.

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Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes

Biomolecules ◽

10.3390/biom10030409 ◽

2020 ◽

Vol 10 (3) ◽

pp. 409 ◽

Cited By ~ 2

Author(s):

Violetta Mohos ◽

Eszter Fliszár-Nyúl ◽

Beáta Lemli ◽

Balázs Zoltán Zsidó ◽

Csaba Hetényi ◽

...

Keyword(s):

Cytochrome P450 ◽

Human Serum Albumin ◽

Serum Albumin ◽

Human Serum ◽

In Vitro Study ◽

Limited Information ◽

Cytochrome P450 Enzymes ◽

Flavonoid Aglycones ◽

Pharmacokinetic Interactions

Flavonoids are abundant polyphenols in nature. They are extensively biotransformed in enterocytes and hepatocytes, where conjugated (methyl, sulfate, and glucuronide) metabolites are formed. However, bacterial microflora in the human intestines also metabolize flavonoids, resulting in the production of smaller phenolic fragments (e.g., hydroxybenzoic, hydroxyacetic and hydroxycinnamic acids, and hydroxybenzenes). Despite the fact that several colonic metabolites appear in the circulation at high concentrations, we have only limited information regarding their pharmacodynamic effects and pharmacokinetic interactions. Therefore, in this in vitro study, we investigated the interactions of 24 microbial flavonoid metabolites with human serum albumin and cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes. Our results demonstrated that some metabolites (e.g., 2,4-dihydroxyacetophenone, pyrogallol, O-desmethylangolensin, and 2-hydroxy-4-methoxybenzoic acid) form stable complexes with albumin. However, the compounds tested did not considerably displace Site I and II marker drugs from albumin. All CYP isoforms examined were significantly inhibited by O-desmethylangolensin; nevertheless, only its effect on CYP2C9 seems to be relevant. Furthermore, resorcinol and phloroglucinol showed strong inhibitory effects on CYP3A4. Our results demonstrate that, besides flavonoid aglycones and their conjugated derivatives, some colonic metabolites are also able to interact with proteins involved in the pharmacokinetics of drugs.

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