The impact of pharmacogenomics on postoperative nausea and vomiting

Do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis?

Keith A. Candiotti, David J. Birnbach, David Lubarsky, Fani Nhuch, Aimee Kamat, Walter H. Koch, Michele Nikoloff, Lin Wu, David Andrews

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Background: Some patients treated with ondansetron for postoperative nausea and vomiting do not respond to therapy. One possible mechanism for this failure is ultrarapid drug metabolism via the cytochrome P-450 system, specifically the enzyme 2D6 (CYP2D6). Ultrarapid metabolism is seen in patients with multiple functional copies (≥ 3) of the CYP2D6 allele. This study was designed to determine whether patients who were given prophylactic ondansetron and had multiple CYP2D6 alleles had an increased rate of postoperative nausea and vomiting. Methods: Two hundred fifty female patients undergoing standardized general anesthesia were given 4 mg ondansetron 30 min before extubation. Patients were observed for symptoms of nausea and vomiting. DNA was extracted from blood in all patients and was analyzed by using a gene-specific probe to determine the CYP2D6 gene copy number and genotyped by polymerase chain reaction amplification with a custom oligonucleotide microarray to determine the specific CYP2D6 genotypes. Results: Eighty-eight patients experienced nausea, and 37 of those patients also had vomiting. In patients with one, two, or three CYP2D6 copies, the incidences of vomiting were 3 in 33 (27%), 27 in 198 (14%), and 7 in 23 (30%), respectively. The incidence of vomiting in subjects with three CYP2D6 copies was significantly different from those with two copies, but not from those with one copy. When analyzed by genotype, the incidences of vomiting in poor, intermediate, extensive, and ultrarapid metabolizers were 1 in 12 (8%), 5 in 30 (17%), 26 in 176 (15%), and 5 in 11 (45%), respectively (P < 0.01 vs. all other groups). There were no differences between groups in the incidence of nausea based on CYP2D6 copy number or genotype. Conclusions: Patients with three copies of the CYP2D6 gene, a genotype consistent with ultrarapid metabolism, or both have an increased incidence of ondansetron failure for the prevention of postoperative vomiting but not nausea.

Original languageEnglish (US)
Pages (from-to)543-549
Number of pages7
JournalAnesthesiology
Volume102
Issue number3
DOIs
StatePublished - Mar 1 2005
Externally publishedYes

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DNA Copy Number Variations
Ondansetron
Postoperative Nausea and Vomiting
Cytochrome P-450 CYP2D6
Pharmacogenetics
Alleles
Vomiting
Genotype
Incidence
Nausea
Gene Dosage
Oligonucleotide Array Sequence Analysis
Cytochrome P-450 Enzyme System
General Anesthesia
Genes

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

The impact of pharmacogenomics on postoperative nausea and vomiting : Do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? / Candiotti, Keith A.; Birnbach, David J.; Lubarsky, David; Nhuch, Fani; Kamat, Aimee; Koch, Walter H.; Nikoloff, Michele; Wu, Lin; Andrews, David.

In: Anesthesiology, Vol. 102, No. 3, 01.03.2005, p. 543-549.

Research output: Contribution to journalArticle

Candiotti, Keith A. ; Birnbach, David J. ; Lubarsky, David ; Nhuch, Fani ; Kamat, Aimee ; Koch, Walter H. ; Nikoloff, Michele ; Wu, Lin ; Andrews, David. / The impact of pharmacogenomics on postoperative nausea and vomiting : Do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis?. In: Anesthesiology. 2005 ; Vol. 102, No. 3. pp. 543-549.
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abstract = "Background: Some patients treated with ondansetron for postoperative nausea and vomiting do not respond to therapy. One possible mechanism for this failure is ultrarapid drug metabolism via the cytochrome P-450 system, specifically the enzyme 2D6 (CYP2D6). Ultrarapid metabolism is seen in patients with multiple functional copies (≥ 3) of the CYP2D6 allele. This study was designed to determine whether patients who were given prophylactic ondansetron and had multiple CYP2D6 alleles had an increased rate of postoperative nausea and vomiting. Methods: Two hundred fifty female patients undergoing standardized general anesthesia were given 4 mg ondansetron 30 min before extubation. Patients were observed for symptoms of nausea and vomiting. DNA was extracted from blood in all patients and was analyzed by using a gene-specific probe to determine the CYP2D6 gene copy number and genotyped by polymerase chain reaction amplification with a custom oligonucleotide microarray to determine the specific CYP2D6 genotypes. Results: Eighty-eight patients experienced nausea, and 37 of those patients also had vomiting. In patients with one, two, or three CYP2D6 copies, the incidences of vomiting were 3 in 33 (27{\%}), 27 in 198 (14{\%}), and 7 in 23 (30{\%}), respectively. The incidence of vomiting in subjects with three CYP2D6 copies was significantly different from those with two copies, but not from those with one copy. When analyzed by genotype, the incidences of vomiting in poor, intermediate, extensive, and ultrarapid metabolizers were 1 in 12 (8{\%}), 5 in 30 (17{\%}), 26 in 176 (15{\%}), and 5 in 11 (45{\%}), respectively (P < 0.01 vs. all other groups). There were no differences between groups in the incidence of nausea based on CYP2D6 copy number or genotype. Conclusions: Patients with three copies of the CYP2D6 gene, a genotype consistent with ultrarapid metabolism, or both have an increased incidence of ondansetron failure for the prevention of postoperative vomiting but not nausea.",
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T2 - Do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis?

AU - Candiotti, Keith A.

AU - Birnbach, David J.

AU - Lubarsky, David

AU - Nhuch, Fani

AU - Kamat, Aimee

AU - Koch, Walter H.

AU - Nikoloff, Michele

AU - Wu, Lin

AU - Andrews, David

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N2 - Background: Some patients treated with ondansetron for postoperative nausea and vomiting do not respond to therapy. One possible mechanism for this failure is ultrarapid drug metabolism via the cytochrome P-450 system, specifically the enzyme 2D6 (CYP2D6). Ultrarapid metabolism is seen in patients with multiple functional copies (≥ 3) of the CYP2D6 allele. This study was designed to determine whether patients who were given prophylactic ondansetron and had multiple CYP2D6 alleles had an increased rate of postoperative nausea and vomiting. Methods: Two hundred fifty female patients undergoing standardized general anesthesia were given 4 mg ondansetron 30 min before extubation. Patients were observed for symptoms of nausea and vomiting. DNA was extracted from blood in all patients and was analyzed by using a gene-specific probe to determine the CYP2D6 gene copy number and genotyped by polymerase chain reaction amplification with a custom oligonucleotide microarray to determine the specific CYP2D6 genotypes. Results: Eighty-eight patients experienced nausea, and 37 of those patients also had vomiting. In patients with one, two, or three CYP2D6 copies, the incidences of vomiting were 3 in 33 (27%), 27 in 198 (14%), and 7 in 23 (30%), respectively. The incidence of vomiting in subjects with three CYP2D6 copies was significantly different from those with two copies, but not from those with one copy. When analyzed by genotype, the incidences of vomiting in poor, intermediate, extensive, and ultrarapid metabolizers were 1 in 12 (8%), 5 in 30 (17%), 26 in 176 (15%), and 5 in 11 (45%), respectively (P < 0.01 vs. all other groups). There were no differences between groups in the incidence of nausea based on CYP2D6 copy number or genotype. Conclusions: Patients with three copies of the CYP2D6 gene, a genotype consistent with ultrarapid metabolism, or both have an increased incidence of ondansetron failure for the prevention of postoperative vomiting but not nausea.

AB - Background: Some patients treated with ondansetron for postoperative nausea and vomiting do not respond to therapy. One possible mechanism for this failure is ultrarapid drug metabolism via the cytochrome P-450 system, specifically the enzyme 2D6 (CYP2D6). Ultrarapid metabolism is seen in patients with multiple functional copies (≥ 3) of the CYP2D6 allele. This study was designed to determine whether patients who were given prophylactic ondansetron and had multiple CYP2D6 alleles had an increased rate of postoperative nausea and vomiting. Methods: Two hundred fifty female patients undergoing standardized general anesthesia were given 4 mg ondansetron 30 min before extubation. Patients were observed for symptoms of nausea and vomiting. DNA was extracted from blood in all patients and was analyzed by using a gene-specific probe to determine the CYP2D6 gene copy number and genotyped by polymerase chain reaction amplification with a custom oligonucleotide microarray to determine the specific CYP2D6 genotypes. Results: Eighty-eight patients experienced nausea, and 37 of those patients also had vomiting. In patients with one, two, or three CYP2D6 copies, the incidences of vomiting were 3 in 33 (27%), 27 in 198 (14%), and 7 in 23 (30%), respectively. The incidence of vomiting in subjects with three CYP2D6 copies was significantly different from those with two copies, but not from those with one copy. When analyzed by genotype, the incidences of vomiting in poor, intermediate, extensive, and ultrarapid metabolizers were 1 in 12 (8%), 5 in 30 (17%), 26 in 176 (15%), and 5 in 11 (45%), respectively (P < 0.01 vs. all other groups). There were no differences between groups in the incidence of nausea based on CYP2D6 copy number or genotype. Conclusions: Patients with three copies of the CYP2D6 gene, a genotype consistent with ultrarapid metabolism, or both have an increased incidence of ondansetron failure for the prevention of postoperative vomiting but not nausea.

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