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



In a cohort of 109 metastatic colorectal cancer patients treated with irinotecan (180 mg/m(2)) 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.



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).



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.
Laboratoire de biochimie, Centre Hospitalier Universitaire de Nîmes, Hôpital Carémeau, Place du Professeur Robert Debré, 30029, Nîmes Cedex 9, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier, France.|Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France.
Litaty Céphanoée
LC
Mbatchi
INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France.
Jacques
J
Robert
IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier, France.|Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
Marc
M
Ychou
Laboratoire de biochimie, Centre Hospitalier Universitaire de Nîmes, Hôpital Carémeau, Place du Professeur Robert Debré, 30029, Nîmes Cedex 9, France.
Jean-Christophe
JC
Boyer
IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier, France.
Maguy
M
Del Rio
Laboratoire de biochimie, Centre Hospitalier Universitaire de Nîmes, Hôpital Carémeau, Place du Professeur Robert Debré, 30029, Nîmes Cedex 9, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier, France.
Matthieu
M
Gassiot
EA4553 Institut Claudius-Regaud, and Université Paul-Sabatier, Toulouse, France.
Fabienne
F
Thomas
Centre Hospitalier Universitaire de Limoges, Limoges Cedex, France.
Nicole
N
Tubiana
Laboratoire de biochimie, Centre Hospitalier Universitaire de Nîmes, Hôpital Carémeau, Place du Professeur Robert Debré, 30029, Nîmes Cedex 9, France. alexandre.evrard@umontpellier.fr.|IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier, France. alexandre.evrard@umontpellier.fr.|Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France. alexandre.evrard@umontpellier.fr.
Alexandre
A
Evrard
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000633:toxicity; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D000090702:Constitutive Androstane Receptor; D004347:Drug Interactions; D005260:Female; D005602:France / Q000453:epidemiology; D005819:Genetic Markers; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011237:Predictive Value of Tests; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics; D015262:Xenobiotics
D000972:Antineoplastic Agents, Phytogenic; D000090702:Constitutive Androstane Receptor; D005819:Genetic Markers; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D000077146:Irinotecan; D002166:Camptothecin