Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: irinotecan Study Group. N Engl J Med. 2000;343(13):905–14.

    Article  CAS  PubMed  Google Scholar 

  2. Ychou M, Viret F, Kramar A, Desseigne F, Mitry E, Guimbaud R, et al. Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases. Cancer Chemother Pharmacol. 2008;62(2):195–201.

    Article  CAS  PubMed  Google Scholar 

  3. Innocenti F, Schilsky RL, Ramírez J, Janisch L, Undevia S, House LK, et al. Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol. 2014;32(22):2328–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kim KP, Hong YS, Lee JL, Bae KS, Kim HS, Shin JG, et al. A phase I study of UGT1A1 *28/*6 genotype-directed dosing of irinotecan (CPT-11) in Korean patients with metastatic colorectal cancer receiving FOLFIRI. Oncology. 2015;88(3):164–72.

    Article  CAS  PubMed  Google Scholar 

  5. Smith NF, Figg WD, Sparreboom A. Pharmacogenetics of irinotecan metabolism and transport: an update. Toxicol In Vitro. 2006;20(2):163–75.

    Article  CAS  PubMed  Google Scholar 

  6. Mohelnikova-Duchonova B, Melichar B, Soucek P. FOLFOX/FOLFIRI pharmacogenetics: the call for a personalized approach in colorectal cancer therapy. World J Gastroenterol. 2014;20(30):10316–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Daniella Lowenberg CFT, Whirl-Carrillo M, Ramirez J, Gong L, Marsh S, Schuetz EG, Dolan ME, Innocenti F, McLeod HL, Ratain MJ. PharmGKB: irinotecan pathway, pharmacokinetics. https://www.pharmgkb.org/pathway/PA2001#PGG. Accessed 20 Mar 2016.

  8. Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res. 2001;7(8):2182–94.

    CAS  PubMed  Google Scholar 

  9. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci USA. 1998;95(14):8170–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen Y, Tang Y, Guo C, Wang J, Boral D, Nie D. Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. Biochem Pharmacol. 2012;83(8):1112–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tolson AH, Wang H. Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev. 2010;62(13):1238–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Staudinger JL, Woody S, Sun M, Cui W. Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver. Drug Metab Rev. 2013;45(1):48–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xie W, Uppal H, Saini SP, Mu Y, Little JM, Radominska-Pandya A, et al. Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism. Drug Discov Today. 2004;9(10):442–9.

    Article  CAS  PubMed  Google Scholar 

  14. Blumberg B, Sabbagh W, Juguilon H, Bolado J, van Meter CM, Ong ES, et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 1998;12(20):3195–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, et al. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci USA. 1998;95(21):12208–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Goodwin B, Hodgson E, D’Costa DJ, Robertson GR, Liddle C. Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol Pharmacol. 2002;62(2):359–65.

    Article  CAS  PubMed  Google Scholar 

  17. Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, et al. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem. 2000;275(20):15122–7.

    Article  CAS  PubMed  Google Scholar 

  18. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 1998;102(5):1016–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lamba J, Lamba V, Strom S, Venkataramanan R, Schuetz E. Novel single nucleotide polymorphisms in the promoter and intron 1 of human pregnane X receptor/NR1I2 and their association with CYP3A4 expression. Drug Metab Dispos. 2008;36(1):169–81.

    Article  CAS  PubMed  Google Scholar 

  20. Luo G, Cunningham M, Kim S, Burn T, Lin J, Sinz M, et al. CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos. 2002;30(7):795–804.

    Article  CAS  PubMed  Google Scholar 

  21. Staudinger JL, Xu C, Cui YJ, Klaassen CD. Nuclear receptor-mediated regulation of carboxylesterase expression and activity. Expert Opin Drug Metab Toxicol. 2010;6(3):261–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Albermann N, Schmitz-Winnenthal FH, Z’graggen K, Volk C, Hoffmann MM, Haefeli WE, et al. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol. 2005;70(6):949–58.

    Article  CAS  PubMed  Google Scholar 

  23. Evrard A, Mbatchi L. Genetic polymorphisms of drug metabolizing enzymes and transporters: the long way from bench to bedside. Curr Top Med Chem. 2012;12(15):1720–9.

    Article  CAS  PubMed  Google Scholar 

  24. Raynal C, Pascussi JM, Leguelinel G, Breuker C, Kantar J, Lallemant B, et al. Pregnane X Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation. Mol Cancer. 2010;9:46.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A. Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst. 2002;94(16):1247–9.

    Article  CAS  PubMed  Google Scholar 

  26. Crews KR, Stewart CF, Jones-Wallace D, Thompson SJ, Houghton PJ, Heideman RL, et al. Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy. Clin Cancer Res. 2002;8(7):2202–9.

    CAS  PubMed  Google Scholar 

  27. Lamba J, Lamba V, Schuetz E. Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Curr Drug Metab. 2005;6(4):369–83.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang J, Kuehl P, Green ED, Touchman JW, Watkins PB, Daly A, et al. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics. 2001;11(7):555–72.

    Article  CAS  PubMed  Google Scholar 

  29. Oleson L, von Moltke LL, Greenblatt DJ, Court MH. Identification of polymorphisms in the 3′-untranslated region of the human pregnane X receptor (PXR) gene associated with variability in cytochrome P450 3A (CYP3A) metabolism. Xenobiotica. 2010;40(2):146–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sandanaraj E, Lal S, Selvarajan V, Ooi LL, Wong ZW, Wong NS, et al. PXR pharmacogenetics: association of haplotypes with hepatic CYP3A4 and ABCB1 messenger RNA expression and doxorubicin clearance in Asian breast cancer patients. Clin Cancer Res. 2008;14(21):7116–26.

    Article  CAS  PubMed  Google Scholar 

  31. Schipani A, Siccardi M, D’Avolio A, Baietto L, Simiele M, Bonora S, et al. Population pharmacokinetic modeling of the association between 63396C->T pregnane X receptor polymorphism and unboosted atazanavir clearance. Antimicrob Agents Chemother. 2010;54(12):5242–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Siccardi M, D’Avolio A, Baietto L, Gibbons S, Sciandra M, Colucci D, et al. Association of a single-nucleotide polymorphism in the pregnane X receptor (PXR 63396C–>T) with reduced concentrations of unboosted atazanavir. Clin Infect Dis. 2008;47(9):1222–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hauser IA, Kruck S, Gauer S, Nies AT, Winter S, Bedke J, et al. Human pregnane X receptor genotype of the donor but not of the recipient is a risk factor for delayed graft function after renal transplantation. Clin Pharmacol Ther. 2012;91(5):905–16.

    Article  CAS  PubMed  Google Scholar 

  34. Xu CF, Bing NX, Ball HA, Rajagopalan D, Sternberg CN, Hutson TE, et al. Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes. J Clin Oncol. 2011;29(18):2557–64.

    Article  CAS  PubMed  Google Scholar 

  35. Mbatchi LC, Schmitt A, Thomas F, Cazaubon Y, Robert J, Lumbroso S, et al. Polymorphisms in SLCO1B3 and NR1I2 as genetic determinants of hematotoxicity of carboplatin and paclitaxel combination. Pharmacogenomics. 2015;16(13):1439–50.

    Article  CAS  PubMed  Google Scholar 

  36. Swart M, Whitehorn H, Ren Y, Smith P, Ramesar RS, Dandara C. PXR and CAR single nucleotide polymorphisms influence plasma efavirenz levels in South African HIV/AIDS patients. BMC Med Genet. 2012;13:112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP, et al. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res. 2011;17(3):620–9.

    Article  PubMed  Google Scholar 

  38. van Erp NP, Eechoute K, van der Veldt AA, Haanen JB, Reyners AK, Mathijssen RH, et al. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol. 2009;27(26):4406–12.

    Article  PubMed  Google Scholar 

  39. Poujol S, Pinguet F, Ychou M, Abderrahim AG, Duffour J, Bressolle FM. A limited sampling strategy to estimate the pharmacokinetic parameters of irinotecan and its active metabolite, SN-38, in patients with metastatic digestive cancer receiving the FOLFIRI regimen. Oncol Rep. 2007;18(6):1613–1621.

    CAS  PubMed  Google Scholar 

  40. Poujol S, Pinguet F, Malosse F, Astre C, Ychou M, Culine S, et al. Sensitive HPLC-fluorescence method for irinotecan and four major metabolites in human plasma and saliva: application to pharmacokinetic studies. Clin Chem. 2003;49(11):1900–8.

    Article  CAS  PubMed  Google Scholar 

  41. Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res. 1994;54(14):3723–5.

    CAS  PubMed  Google Scholar 

  42. Benkali K, Prémaud A, Picard N, Rérolle JP, Toupance O, Hoizey G, et al. Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients. Clin Pharmacokinet. 2009;48(12):805–16.

    Article  CAS  PubMed  Google Scholar 

  43. Dring MM, Goulding CA, Trimble VI, Keegan D, Ryan AW, Brophy KM, et al. The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease. Gastroenterology. 2006;130(2):341–8 (quiz 592).

    Article  CAS  PubMed  Google Scholar 

  44. Sookoian S, Castaño GO, Burgueño AL, Gianotti TF, Rosselli MS, Pirola CJ. The nuclear receptor PXR gene variants are associated with liver injury in nonalcoholic fatty liver disease. Pharmacogenet Genom. 2010;20(1):1–8.

    Article  CAS  Google Scholar 

  45. Karlsen TH, Lie BA, Frey Frøslie K, Thorsby E, Broomé U, Schrumpf E, et al. Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis. Gastroenterology. 2006;131(3):781–7.

    Article  CAS  PubMed  Google Scholar 

  46. Ferraresso M, Turolo S, Belinghieri M, Tirelli AS, Grillo P, Groppali E, et al. The potential of steroids and xenobiotic receptor polymorphisms in forecasting cyclosporine pharmacokinetic variability in young kidney transplant recipients. Pediatr Transpl. 2012;16(6):658–63.

    Article  CAS  Google Scholar 

  47. Urano T, Usui T, Shiraki M, Ouchi Y, Inoue S. Association of a single nucleotide polymorphism in the constitutive androstane receptor gene with bone mineral density. Geriatr Gerontol Int. 2009;9(3):235–41.

    Article  PubMed  Google Scholar 

  48. Moon JY, Lee KE, Chang BC, Jeong E, Jeong H, Gwak HS. Combined effects of hepatocyte nuclear factor 4α and constitutive androstane receptor on stable warfarin doses. Pharmacogenet Genom. 2015;25(1):38–40.

    Article  CAS  Google Scholar 

  49. Wyen C, Hendra H, Siccardi M, Platten M, Jaeger H, Harrer T, et al. Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens. J Antimicrob Chemother. 2011;66(9):2092–8.

    Article  CAS  PubMed  Google Scholar 

  50. Andersen V, Christensen J, Ernst A, Jacobsen BA, Tjønneland A, Krarup HB, et al. Polymorphisms in NF-κB, PXR, LXR, PPARγ and risk of inflammatory bowel disease. World J Gastroenterol. 2011;17(2):197–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Amre DK, Mack DR, Israel D, Morgan K, Krupoves A, Costea I, et al. Investigation of associations between the pregnane-X receptor gene (NR1I2) and Crohn’s disease in Canadian children using a gene-wide haplotype-based approach. Inflamm Bowel Dis. 2008;14(9):1214–8.

    Article  PubMed  Google Scholar 

  52. Dahan L, Ciccolini J, Evrard A, Mbatchi L, Tibbitts J, Ries P, et al. Sudden death related to toxicity in a patient on capecitabine and irinotecan plus bevacizumab intake: pharmacogenetic implications. J Clin Oncol. 2012;30(4):e41–4.

    Article  CAS  PubMed  Google Scholar 

  53. González JR, Armengol L, Solé X, Guinó E, Mercader JM, Estivill X, et al. SNPassoc: an R package to perform whole genome association studies. Bioinformatics. 2007;23(5):644–5.

    Article  PubMed  Google Scholar 

  54. John Storey AB, Dabney A, Robinson D. qvalue: Q-value estimation for false discovery rate control. R package version 2.0.0. http://qvalue.princeton.edu/, http://github.com/jdstorey/qvalue. Accessed 20 Feb 2016.

  55. Yoav B, Yosef H. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc Series B (Methodological). 1995;1995(57):289–300.

    Google Scholar 

  56. Chen JJ, Roberson PK, Schell MJ. The false discovery rate: a key concept in large-scale genetic studies. Cancer Control. 2010;17(1):58–62.

    PubMed  Google Scholar 

  57. Sinnwell JP SD. haplo.stats: Statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous. 2015. https://cran.r-project.org/web/packages/haplo.stats/index.html. Accessed 10 Oct 2015.

  58. NCBI. dbSNP: Database of single nucleotide polymorphisms (SNPs) and multiple small-scale variations that include insertions/deletions, microsatellites, and non-polymorphic variants. http://www.ncbi.nlm.nih.gov/SNP/. Accessed 10 Oct 2015.

  59. Marsh S, Hoskins JM. Irinotecan pharmacogenomics. Pharmacogenomics. 2010;11(7):1003–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mathijssen RH, Gurney H. Irinogenetics: how many stars are there in the sky? J Clin Oncol. 2009;27(16):2578–9.

    Article  CAS  PubMed  Google Scholar 

  61. Sai K, Saito Y, Tatewaki N, Hosokawa M, Kaniwa N, Nishimaki-Mogami T, et al. Association of carboxylesterase 1A genotypes with irinotecan pharmacokinetics in Japanese cancer patients. Br J Clin Pharmacol. 2010;70(2):222–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Carlini LE, Meropol NJ, Bever J, Andria ML, Hill T, Gold P, et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res. 2005;11(3):1226–36.

    CAS  PubMed  Google Scholar 

  63. Chen S, Laverdiere I, Tourancheau A, Jonker D, Couture F, Cecchin E, et al. A novel UGT1 marker associated with better tolerance against irinotecan-induced severe neutropenia in metastatic colorectal cancer patients. Pharmacogenomics J. 2015;15(6):513–20.

    Article  CAS  PubMed  Google Scholar 

  64. Crona DJ, Ramirez J, Qiao W, de Graan AJ, Ratain MJ, van Schaik RH, et al. Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study. Pharmacogenomics J. 2016;16(1):54–9.

    Article  CAS  PubMed  Google Scholar 

  65. Etienne-Grimaldi MC, Boyer JC, Thomas F, Quaranta S, Picard N, Loriot MA, et al. UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice. Fundam Clin Pharmacol. 2015;29(3):219–37.

    Article  CAS  PubMed  Google Scholar 

  66. Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst. 2007;99(17):1290–5.

    Article  CAS  PubMed  Google Scholar 

  67. Huang L, Zhang T, Xie C, Liao X, Yu Q, Feng J, et al. SLCO1B1 and SLC19A1 gene variants and irinotecan-induced rapid response and survival: a prospective multicenter pharmacogenetics study of metastatic colorectal cancer. PLoS One. 2013;8(10):e77223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. De Mattia E, Toffoli G, Polesel J, D’Andrea M, Corona G, Zagonel V, et al. Pharmacogenetics of ABC and SLC transporters in metastatic colorectal cancer patients receiving first-line FOLFIRI treatment. Pharmacogenet Genom. 2013;23(10):549–57.

    Article  Google Scholar 

  69. Kile DA, MaWhinney S, Aquilante CL, Rower JE, Castillo-Mancilla JR, Anderson PL. A population pharmacokinetic-pharmacogenetic analysis of atazanavir. AIDS Res Hum Retroviruses. 2012;28(10):1227–34.

    Article  CAS  PubMed  Google Scholar 

  70. Bonora S, Rusconi S, Calcagno A, Bracchi M, Viganò O, Cusato J, et al. Successful pharmacogenetics-based optimization of unboosted atazanavir plasma exposure in HIV-positive patients: a randomized, controlled, pilot study (the REYAGEN study). J Antimicrob Chemother. 2015;70(11):3096–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratoire de biochimie, Centre Hospitalier Universitaire de Nîmes, Hôpital Carémeau, Place du Professeur Robert Debré, 30029, Nîmes Cedex 9, France

    Litaty Céphanoée Mbatchi, Jean-Christophe Boyer, Matthieu Gassiot & Alexandre Evrard

  2. IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier, France

    Litaty Céphanoée Mbatchi, Marc Ychou, Maguy Del Rio, Matthieu Gassiot & Alexandre Evrard

  3. Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France

    Litaty Céphanoée Mbatchi & Alexandre Evrard

  4. INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France

    Jacques Robert

  5. Institut Régional du Cancer de Montpellier (ICM)-Val d’Aurelle, Montpellier, France

    Marc Ychou

  6. EA4553 Institut Claudius-Regaud, and Université Paul-Sabatier, Toulouse, France

    Fabienne Thomas

  7. Centre Hospitalier Universitaire de Limoges, Limoges Cedex, France

    Nicole Tubiana

Authors
  1. Litaty Céphanoée Mbatchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacques Robert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc Ychou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Christophe Boyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maguy Del Rio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthieu Gassiot
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fabienne Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nicole Tubiana
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alexandre Evrard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexandre Evrard.

Ethics declarations

Funding

This work was supported by a Grant from the Centre Hospitalier Universitaire de Nîmes (France) and a grant from Cancéropôle Grand Sud-Ouest (France).

Conflicts of interest

Litaty Céphanoée Mbatchi, Jacques Robert, Marc Ychou, Jean-Christophe Boyer, Maguy Del Rio, Matthieu Gassiot, Fabienne Thomas, Nicole Tubiana, and Alexandre Evrard declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mbatchi, L.C., Robert, J., Ychou, M. et al. Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients. Clin Pharmacokinet 55, 1145–1157 (2016). https://doi.org/10.1007/s40262-016-0392-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-016-0392-5

Keywords

Search

Navigation