title: Association of ABCB1 polymorphisms with the efficacy of ondansetron in chemotherapy-induced nausea and vomiting.
abstract: OBJECTIVE
  Resistance to the antiemetic ondansetron is still a major problem resulting in discomfort and poor compliance with chemotherapy in acute myeloid leukemia (AML) patients. Based on our hypothesis that this clinical resistance to ondansetron is associated with ABCB1 genetic polymorphisms, we investigated whether ABCB1 gene variations affect the efficacy of ondansetron in chemotherapy-induced nausea and vomiting.
  
  
  METHODS
  AML patients (n = 215) treated for 3 days with high-dose cytarabine were enrolled in this study. Thirty minutes before the beginning of chemotherapy, 8 mg ondansetron was administered intravenously, followed by 24 mg by continuous infusion and 8 mg intravenously, once per day, until 2 days after chemotherapy. Chemotherapy-induced nausea and vomiting occurrence in the acute and delayed phases was calculated. ABCB1 and CYP2D6 polymorphisms were analyzed by allele-specific matrix-assisted laser desorption. Basic clinical characteristics of the AML patients were collected from medical records.
  
  
  RESULTS
  No differences in genotype distribution frequencies of ABCB1 polymorphisms and haplotypes were observed in patients with different CYP2D6-predicted phenotypes. During the acute phase, patients with the CG haplotype (C3435T and G2677T) were associated with a high risk of grade 3/4 nausea and vomiting (P = 0.003 and P = 0.026, respectively). After adjustment for age, sex, smoking status, alcohol drinking status, body surface area, body mass index, and Eastern Cooperative Oncology Group-Performance Status, multivariate survival analysis implicated the CG haplotype as a predictive marker of the risk of grade 3/4 chemotherapy-induced nausea and vomiting in AML patients (P = 0.003 and P = 0.039, respectively). In addition, a significant association between the 3435CC genotype and grade 3/4 vomiting in AML patients was observed (P = 0.016). However, no association between these ABCB1 gene polymorphisms and ondansetron efficacy was found in the delayed phase.
  
  
  CONCLUSIONS
  These findings suggest that ABCB1 gene polymorphisms are associated with antiemetic efficacy of ondansetron in the acute phase after high-dose cytarabine chemotherapy in AML patients.
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University, Changsha, China; Hunan Key Laboratory of Pharmacogenetics, Changsha, China; Department of Hematology, Benxi Central Hospital of China Medical University, Benxi, China.
authors.forename: Hui
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University, Changsha, China; Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Yin
authors.affiliation: Department of Hematology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University, Changsha, China; Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University, Changsha, China; Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shengjing Hospital, China Medical University, Shenyang, China.
authors.forename: Zhuo-Gang
authors.initials: ZG
authors.lastname: Liu
authors.affiliation: Deparment of Hematology, General Hospital of Shenyang Military Area Command, Shenyang, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Hematology, The First Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhai
authors.affiliation: Department of Hematology, The First Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University, Changsha, China; Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Li
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University, Changsha, China; Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University, Changsha, China; Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University, Changsha, China; Hunan Key Laboratory of Pharmacogenetics, Changsha, China. Electronic address: liuzhaoqian63@126.com.
authors.forename: Zhao-Qian
authors.initials: ZQ
authors.lastname: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000932:Antiemetics / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D017294:Ondansetron / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000932:Antiemetics; D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D017294:Ondansetron; D019389:Cytochrome P-450 CYP2D6
keywords: ABCB1; cytarabine; efficacy; genetic polymorphism; ondansetron