Metronidazole reduces the expression of cytochrome P450 enzymes in HepaRG cells and cryopreserved human hepatocytes

  title={Metronidazole reduces the expression of cytochrome P450 enzymes in HepaRG cells and cryopreserved human hepatocytes},
  author={Toshiyuki Kudo and Y. Endo and Rina Taguchi and Masami Yatsu and Kiyomi Ito},
  pages={413 - 419}
Abstract 1. Blood levels of S-warfarin have been reported to be increased by concomitant administration of metronidazole (MTZ), an antiprotozoal imidazole derivative. 2. To elucidate the mechanism of this interaction and to identify other possible drug-drug interactions, we conducted an in vitro study with the human hepatoma HepaRG cells and cryopreserved human hepatocytes on the ability of MTZ to reduce the expression of cytochrome P450 (CYP) as well as nuclear receptors that regulate the… 

Xenobiotic Metabolising Enzymes: Impact on Pathologic Conditions, Drug Interactions and Drug Design.

Study of drug metabolism is of major importance for the development of drugs and provides insight into the control of human health, and some of the previous research results are presented, which may assist in the elucidation of xenobiotic metabolism and in thedevelopment of more efficient drugs.

The different metabolism of morusin in various species and its potent inhibition against UDP-glucuronosyltransferase (UGT) and cytochrome p450 (CYP450) enzymes

This study provided vital information to understand the inhibitory potential and metabolic behavior of morusin among various species and exhibited significant species differences.


Pharmacokinetic-pharmacodynamic translation can be optimally achieved by incorporating newly derived Michaelis-Menten equations into pharmacokinetic parameters for clinical efficacy and safety of therapeutics.

Application of modified Michaelis – Menten equations for determination of enzyme inducing and inhibiting drugs

  • S. Saganuwan
  • Biology, Chemistry
    BMC pharmacology & toxicology
  • 2021
Pharmacokinetic-pharmacodynamic translation can be optimally achieved by incorporating, newly modified Michaelis-Menten equations into pharmacokinetic formulas for clinical efficacy and safety of the enzyme inducing and inhibiting therapeutic agents used in laboratory and clinical settings.

Optimized HepaRG is a suitable cell source to generate the human liver chimeric mouse model for the chronic hepatitis B virus infection

The experimental results showed that the liver chimerism of the mice was adequate to support chronic HBV infection for 24 weeks and to evaluate antivirals, and overall, HepaRG-FRGS mice provide a novel human liver chimeric mouse model to study chronicHBV infection and evaluate anti-HBV drugs.

Degradation of Metronidazole Antibiotic Using a Novel Synthesised Magnetic Nanocomposite in Heterogeneous Fenton-like Catalytic Process

Antibiotics are organic pollutants that are introduced into surface water and underground water sources due to urban and industrial effluents. Due to their high stability, they do not only disrupt

Drug-drug interactions with metronidazole and itraconazole in patients using acenocoumarol

Co-trimoxazole, metronidazoles, and itraconazole increase the risk of overanticoagulation in patients using acenocoumarol, and these combinations should be avoided if possible or otherwise acenOCou marol doses should be reduced and INR measured more frequently.

Drug-drug interactions with metronidazole and itraconazole in patients using acenocoumarol

Purpose Various population-based cohort studies have shown that antimicrobial agents increase the risk of overanticoagulation in patients using coumarins. In this study, we assessed this association

Drug Interactions Affecting Oral Anticoagulant Use

DDI for warfarin mainly involve moderate to strong inhibitors/inducers of cytochrome P450 (CYP) 2C9, which is responsible for the elimination of the more potent S-isomer of warfar in patients with atrial fibrillation and other cardiovascular conditions.

Exome sequencing allows detection of relevant pharmacogenetic variants in epileptic patients

In epileptic patients, pangenomic sequencing can provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high plasma levels.



Stable Expression, Activity, and Inducibility of Cytochromes P450 in Differentiated HepaRG Cells

The data support the conclusion that HepaRG cells represent a promising surrogate to primary human hepatocytes for xenobiotic metabolism and toxicity studies and a good correlation was observed between transcript levels and corresponding activities.

HepaRG Cells as an in Vitro Model for Evaluation of Cytochrome P450 Induction in Humans

The present study shows that HepaRG cells are a valuable model to be used for prediction of induction of drug-metabolizing P450 enzymes in vivo in humans.

Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture

  • M. MauriceL. Pichard P. Maurel
  • Biology, Chemistry
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 1992
Analysis of the expression of several forms of cytochrome P450 in human hepatocytes maintained in primary culture revealed that ketoconazole was a strong and selective in vitro inhibitor of P450 3A (cyclosporin oxidase) with a Ki < 1 μm.


HepaRG cells constitute the first human hepatoma cell line expressing high levels of the major P450s involved in xenobiotic metabolism and represent a reliable surrogate to human hepatocytes for drug metabolism and toxicity studies.

Effects of metronidazole on midazolam metabolism in vitro and in vivo

Findings indicate that metronidazole is not an inhibitor of CYP3A4, using midazolam as a model substrate in vitro and in vivo.

Ketoconazole and Miconazole Are Antagonists of the Human Glucocorticoid Receptor: Consequences on the Expression and Function of the Constitutive Androstane Receptor and the Pregnane X Receptor

Ketoconazole and miconazole are antagonists of hGR, providing a novel molecular mechanism by which these compounds may exert adverse and toxic effects on drug metabolism and other functions in human.

Azole Antimycotics Differentially Affect Rifampicin-Induced Pregnane X Receptor-Mediated CYP3A4 Gene Expression

It is suggested that the ability of some azoles to affect recruitment of SRC-1 to PXR modulates their net effects in transactivation of CYP3A4 both in the absence or presence of rifampicin.

Investigation of the safety of topical metronidazole from a pharmacokinetic perspective.

Results suggest that the reported interaction of oral MTZ and S-warfarin was not due to CYP2C9 inhibition and that drug interactions via inhibition of CYP1C9 is unlikely to occur when MTZ ointment is applied to ulcerous skin.

Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions.

It is concluded that 2C9 is likely to be a principal form of human liver P-450 which modulates the in vivo anticoagulant activity of the drug.

Inhibition and induction of human cytochrome P450 enzymes: current status

This review covers both inhibition and induction of CYP enzymes, always keeping in mind the basic mechanisms on which to build predictive and preventive in vitro approaches.