Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate.
Article Details
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Nallani SC, Glauser TA, Hariparsad N, Setchell K, Buckley DJ, Buckley AR, Desai PB
Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate.
Epilepsia. 2003 Dec;44(12):1521-8.
- PubMed ID
- 14636322 [ View in PubMed]
- Abstract
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. METHODS: Human hepatocytes were treated for 72 h with TPM (10, 25, 50, 100, 250, and 500 microM) and known inducers, phenobarbital (PB; 2 mM), and rifampicin (10 microM). The rate of testosterone 6beta-hydroxylation by hepatocytes served as a marker for CYP3A4 activity. The CYP3A4-specific protein and mRNA levels were determined by using Western and Northern blot analyses, respectively. The hPXR activation was assessed with cell-based reporter gene assay. RESULTS: Compared with controls, TPM (50-500 microM)-treated hepatocytes exhibited a considerable increase in the CYP3A4 activity (1. 6- to 8.2-fold), protein levels (4.6- to 17.3-fold), and mRNA levels (1.9- to 13.3-fold). Comparatively, rifampicin (10 microM) effected 14.5-, 25.3-, and a 20.3-fold increase in CYP3A4 activity, immunoreactive protein levels, and mRNA levels, respectively. TPM (50-500 microM) caused 1.3- to 3-fold activation of the hPXR, whereas rifampicin (10 microM) caused a 6-fold activation. CONCLUSIONS: The observed induction of CYP3A4 by TPM, especially at the higher concentrations, provides a potential mechanistic explanation of the reported increase in the ethinyl estradiol clearance by TPM. It also is suggestive of other potential interactions when high-dose TPM therapy is used.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Barbital Cytochrome P450 3A4 Protein Humans NoInducerDetails Topiramate Cytochrome P450 3A4 Protein Humans UnknownInducerDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your software- Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Rifampicin Approved CYP3A4 1576 upregulated Rifampin results in increased expression of CYP3A4 mRNA 7q22.1 Topiramate Approved CYP3A4 1576 upregulated topiramate results in increased expression of CYP3A4 mRNA 7q22.1 - Pharmaco-proteomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1 Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1 Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1