Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

  title={Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate},
  author={Srikanth C. Nallani and Tracy A. Glauser and Niresh Hariparsad and Kenneth D. R. Setchell and Donna J. Buckley and Arthur R. Buckley and Pankaj B. Desai},
Summary:  Purpose: In clinical studies, topiramate (TPM) was shown to cause a dose‐dependent increase in the clearance of ethinyl estradiol. We hypothesized that this interaction results from induction of hepatic cytochrome P450 (CYP) 3A4 by TPM. Accordingly, we investigated whether TPM induces CYP3A4 in primary human hepatocytes and activates the human pregnane X receptor (hPXR), a nuclear receptor that serves as a regulator of CYP3A4 transcription. 

Synthetic Drugs and Natural Products as Modulators of Constitutive Androstane Receptor (Car) and Pregnane X Receptor (PXR)

The importance of these receptors for pharmacology and toxicology is discussed, emphasizing the role of individual drugs and natural products as agonist, indirect activators, inverse agonists, and antagonists of CAR and PXR.

Opportunities and challenges in using human hepatocytes in cytochromes P450 induction assays

  • Z. Dvořák
  • Biology, Medicine
    Expert opinion on drug metabolism & toxicology
  • 2016
Primary cultures of HHs remain the most suitable model for complex CYP induction studies, and their exploitation for the identification of P450 inducers is provided.

Pharmacokinetic Drug Interactions Between Clobazam and Drugs Metabolized by Cytochrome P450 Isoenzymes

To investigate potential drug‐drug interactions between clobazam and cytochrome P450 (CYP) isoenzyme substrates, inhibitors, and inducers, a chiral stationary phase study is conducted.

Effects of CYP3A4 and P-glycoprotein inhibition or induction on the pharmacokinetics of ubrogepant in healthy adults: Two phase 1, open-label, fixed-sequence, single-center, crossover trials

The PK of ubrogepant were significantly affected by the concomitant use of CYP3A4 moderate-strong inhibitors and strong inducers.

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

The molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences, and assessment of the potential at the drug discovery and development stage will be discussed.

The role of CYP3A4 in the biotransformation of bile acids and therapeutic implication for cholestasis.

Recent progress about the roles of CYP3A4 in the metabolism of bile acids, its regulation and possible implication in the treatment of cholestasis are summarized.

Induction of endogenous pathways by antiepileptics and clinical implications

Modifications of the endogenous pathways (e.g. enzyme elevations, normal body constituent depletion or higher formation/excretion of endogenous metabolites) which could be ascribed to enzyme induction by antiepileptic drugs (AEDs) are reviewed.

Markedly Elevated Carbamazepine-10,11-epoxide/Carbamazepine Ratio in a Fatal Carbamazepine Ingestion

A case of fatal carbamazepine overdose is reported in which the epoxide metabolite concentration was found to be 450% higher than the parent compound, suggesting a potential role for metabolite quantification in severe toxicity.

Enzyme induction with antiepileptic drugs: Cause for concern?

Induction of enzyme‐inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease, and perhaps consideration should be given to starting treatment with, or even switching patients to, non–enzyme‐inducingAEDs.



Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen.

The results indicate that the mechanism of tamoxifen-mediated alteration in drug clearance pathways in humans may involve CYP3A4 induction by the parent drug and/or its metabolite.

The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.

The identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP 3A4 expression is reported.

The Human Nuclear Xenobiotic Receptor PXR: Structural Determinants of Directed Promiscuity

The hydrophobic ligand-binding cavity of hPXR contains a small number of polar residues, permitting SR12813 to bind in three distinct orientations, and the position and nature of these polar residues were found to be critical for establishing the precise pharmacologic activation profile of PXR.

Hepatic but not intestinal CYP3A4 displays dose‐dependent induction by efavirenz in humans

The capacity of the non‐nucleoside reverse transcriptase inhibitor efavirenz to induce either liver CYP3A4 or intestinal CYP3A4, or both, as well as intestinal P‐glycoprotein, was evaluated in

CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes.

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  • Biology, Medicine
    Drug metabolism and disposition: the biological fate of chemicals
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It is concluded that the PXR reporter gene assay is a reliable and complementary method to assess the CYP3A4 induction potential of drugs and other xenobiotics.

Orphan Nuclear Receptors Constitutive Androstane Receptor and Pregnane X Receptor Share Xenobiotic and Steroid Ligands*

It is demonstrated that several of the compounds that regulate mouse and human CAR, including natural steroids, bind directly to the receptors and suggest that CAR, like PXR, is a steroid receptor that is capable of recognizing structurally diverse compounds.

The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution.

PXR is established as a promiscuous xenobiotic receptor that has diverged during evolution through the use of a novel scintillation proximity binding assay, which demonstrates that many of the compounds that induce CYP3A expression bind directly to human PXR.

Increased activity of CYP3A enzyme in primary cultures of rat hepatocytes treated with docetaxel: comparative evaluation with paclitaxel

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The Xenobiotic Compound 1,4-Bis[2-(3,5-Dichloropyridyloxy)]Benzene Is an Agonist Ligand for the Nuclear Receptor CAR

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