title: Association of ABCB1, 5-HT3B receptor and CYP2D6 genetic polymorphisms with ondansetron and metoclopramide antiemetic response in Indonesian cancer patients treated with highly emetogenic chemotherapy.
abstract: OBJECTIVE
  Suboptimal treatment of chemotherapy-induced nausea and vomiting and unsatisfactory response to antiemetic drugs cause impairment of cancer patient's daily functioning. This study was aimed to investigate the association of selected germline polymorphisms with ondansetron and metoclopramide response in Indonesian cancer patients treated with highly emetogenic chemotherapy.
  
  
  METHODS
  We enrolled 202 chemotherapy naïve patients treated with cisplatin at a dosage of ≥50 mg/m(2) as monotherapy or as combined chemotherapy. Ondansetron 8 mg and dexamethasone 8 mg intravenously were the standard antiemetic therapy for prevention of acute chemotherapy-induced nausea and vomiting. Metoclopramide 10 mg orally, three times per day as fixed prescription, was given until 5 days after chemotherapy to prevent delayed chemotherapy-induced nausea and vomiting. Primary and secondary outcomes were the occurrence of chemotherapy-induced nausea and vomiting in the acute and delayed phase. The following single-nucleotide polymorphisms were determined in ABCB1: rs1045642, rs2032582 and rs1128503; in 5-HT3B-R: rs45460698, rs4938058 and rs7943062; and in CYP2D6: rs16947 (CYP2D6 2), rs3892097 (CYP2D6 4) and rs1065852 (CYP2D6 10) using Taqman assays.
  
  
  RESULTS
  During the acute phase, 21.8 and 30.2% patients experienced Grade 3 and 4 nausea and vomiting, respectively, whereas 38.6% patients experienced nausea and/or vomiting in the delayed phase. Carriers of the CTG haplotype of the ABCB1 gene experienced Grade 3 and 4 chemotherapy-induced nausea and vomiting more often than other haplotypes in the delayed phase (P< 0.05). No associations were found with the 5-HT3B receptor haplotypes and CYP2D6-predicted phenotypes.
  
  
  CONCLUSIONS
  Our study shows that in Indonesian cancer patients treated with highly cytostatic emetogenic, carriership of the CTG haplotype of the ABCB1 gene is related to an increased risk of delayed chemotherapy-induced nausea and vomiting.
authors.affiliation: Department of Pharmacy, Ahmad Dahlan University, Yogyakarta, Indonesia.
authors.forename: Dyah A
authors.initials: DA
authors.lastname: Perwitasari
authors.forename: Judith A M
authors.initials: JA
authors.lastname: Wessels
authors.forename: Robert J H M
authors.initials: RJ
authors.lastname: van der Straaten
authors.forename: Renee F
authors.initials: RF
authors.lastname: Baak-Pablo
authors.forename: Mustofa
authors.initials: M
authors.lastname: Mustofa
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hakimi
authors.forename: Johann W R
authors.initials: JW
authors.lastname: Nortier
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000932:Antiemetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007214:Indonesia; D008297:Male; D008787:Metoclopramide / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy; D017294:Ondansetron / Q000493:pharmacokinetics / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics*; D014839:Vomiting / Q000139:chemically induced / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000932:Antiemetics; D000970:Antineoplastic Agents; C509410:HTR3B protein, human; D044406:Receptors, Serotonin, 5-HT3; D017294:Ondansetron; D019389:Cytochrome P-450 CYP2D6; D008787:Metoclopramide; D002945:Cisplatin