| Added by | mollevi |
|---|---|
| Last modified by | celine.gongora |
| Group name | EquipeCG |
| Item Type | Journal Article |
| Title | Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients |
| Creator | Mbatchi et al. |
| Author | L. C. Mbatchi |
| Author | J. Robert |
| Author | M. Ychou |
| Author | J. C. Boyer |
| Author | M. Del Rio |
| Author | M. Gassiot |
| Author | F. Thomas |
| Author | N. Tubiana |
| Author | A. Evrard |
| 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. |
| Publication | Clin Pharmacokinet |
| Date | Apr 26 2016 |
| Journal Abbr | Clinical pharmacokinetics |
| DOI | 10.1007/s40262-016-0392-5 |
| ISSN | 1179-1926 (Electronic) 0312-5963 (Linking) |
| Tags | canceropoleGSO, first, original |
| Date Added | 2018/07/20 - 10:05:58 |
| Date Modified | 2019/10/24 - 17:16:11 |
| Notes and Attachments | (Note) (Note) 27116457 (Attachment) |
Institut de Recherche en Cancérologie de
