Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor

PurposeInduction of cytochrome P450 (CYP) 3A4, an enzyme that is involved in the biotransformation of more than 50% of all drugs, by xenobiotics is an important cause of pharmacokinetic drug–drug interactions in oncology. In addition to rifampicin and hyperforin, the anticancer drug paclitaxel has also been shown to be an inducer of CYP3A4 via activation of the pregnane X receptor (PXR). We therefore screened 18 widely used anticancer drugs for their ability to activate PXR-mediated CYP3A4 induction.MethodsA CYP3A4 reporter gene assay was employed to identify PXR agonists among the eighteen anticancer drugs. Subsequently CYP3A4 mRNA and protein expression following treatment with these PXR agonists was assessed. Finally, the effect of pre-treatment with these agents on the 1’-hydroxylation of midazolam (a specific CYP3A4 probe) was determined.ResultsPaclitaxel, erlotinib, tamoxifen, ifosfamide, flutamide and docetaxel are able to activate PXR, while only strong PXR activation leads to significant induction of CYP3A4 activity.ConclusionsThe identified PXR agonists may have the propensity to cause clinically relevant drug–drug interactions as a result of CYP3A4 induction.

• Publication year

  2009

• Venue

  Cancer Chemotherapy and Pharmacology

• Publication date

  2009-06-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1007/s00280-008-0842-3PMID 18839173
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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