title: ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children.
abstract: Respiratory depression (RD) is a serious side effect of morphine and detrimental to effective analgesia. We reported that variants of the ATP binding cassette gene ABCC3 (facilitates hepatic morphine metabolite efflux) affect morphine metabolite clearance. In this study of 316 children undergoing tonsillectomy, we found significant association between ABCC3 variants and RD leading to prolonged postoperative care unit stay (prolonged RD). Allele A at rs4148412 and allele G at rs729923 caused a 2.36 (95% CI=1.28-4.37, P=0.0061) and 3.7 (95% CI 1.47-9.09, P=0.0050) times increase in odds of prolonged RD, respectively. These clinical associations were supported by increased formation clearance of morphine glucuronides in children with rs4148412 AA and rs4973665 CC genotypes in this cohort, as well as an independent spine surgical cohort of 67 adolescents. This is the first study to report association of ABCC3 variants with opioid-related RD, and morphine metabolite formation (in two independent surgical cohorts).
authors.affiliation: Department of Anesthesia, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: V
authors.initials: V
authors.lastname: Chidambaran
authors.affiliation: Department of Anesthesia, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.|Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Venkatasubramanian
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Department of Anesthesia, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.|Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Niu
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.|Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.|Division of Bioinformatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Meller
authors.affiliation: Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.|Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Vinks
authors.affiliation: Department of Anesthesia, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sadhasivam
mesh_terms: D000233:Adenoidectomy / Q000009:adverse effects; D000293:Adolescent; D000367:Age Factors; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002648:Child; D004334:Drug Administration Schedule; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D020719:Glucuronides / Q000493:pharmacokinetics; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008657:Metabolic Clearance Rate; D050217:Metabolic Detoxication, Phase II; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D016017:Odds Ratio; D019637:Orthopedic Procedures / Q000009:adverse effects; D010149:Postoperative Pain / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011182:Postoperative Care; D011446:Prospective Studies; D012119:Respiration / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D012307:Risk Factors; D013131:Spine / Q000601:surgery; D014068:Tonsillectomy / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D020719:Glucuronides; D009020:Morphine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C114462:multidrug resistance-associated protein 3
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