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Clinical Pharmacokinetics
Erschienen in: Clinical Pharmacokinetics 9/2016

26.04.2016 | Original Research Article

Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients

verfasst von: Litaty Céphanoée Mbatchi, Jacques Robert, Marc Ychou, Jean-Christophe Boyer, Maguy Del Rio, Matthieu Gassiot, Fabienne Thomas, Nicole Tubiana, Alexandre Evrard

Erschienen in: Clinical Pharmacokinetics | Ausgabe 9/2016

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Abstract

Background and Objectives

Nuclear receptors PXR (pregnane X receptor, NR1I2) and CAR (constitutive androstane receptor, NR1I3) are key regulators of irinotecan metabolism, and ligand-dependent modulation of their activity leads to significant drug–drug interactions. Because genetic polymorphisms can also affect the activity of these xenobiotic-sensing receptors, we hypothesized that they could contribute to the interpatient variability of irinotecan pharmacokinetics and to the toxicity of irinotecan-based regimens.

Patients and Methods

In a cohort of 109 metastatic colorectal cancer patients treated with irinotecan (180 mg/m2) in combination with other drugs, associations were assessed between 21 selected single nucleotide polymorphisms of NR1I2 or NR1I3 and pharmacokinetic parameters or toxicity of irinotecan and its metabolites.

Results

After adjustment of the tests by the UGT1A1*28 genotype and correction for multiple testing, the A allele of NR1I2-rs10934498 was associated with a decreased exposition and an increased degradation of SN-38, the active metabolite (p = 0.009 and p = 0.017, respectively). The risk of hematological toxicity was associated with NR1I2-rs10934498 and NR1I2-rs2472677 (p = 0.009 and p = 0.003, respectively).

Conclusion

Our results reveal for the first time the involvement of NR1I2 in the pharmacogenetics of irinotecan and suggest that it may help to predict the toxicity of low-dose irinotecan.
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Metadaten
Titel
Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients
verfasst von
Litaty Céphanoée Mbatchi
Jacques Robert
Marc Ychou
Jean-Christophe Boyer
Maguy Del Rio
Matthieu Gassiot
Fabienne Thomas
Nicole Tubiana
Alexandre Evrard
Publikationsdatum
26.04.2016
Verlag
Springer International Publishing
Erschienen in
Clinical Pharmacokinetics / Ausgabe 9/2016
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0392-5

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