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Pharmacogenomics J. 2017 Mar;17(2):162-169. doi: 10.1038/tpj.2015.98. Epub 2016 Jan 26.

ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children.

Author information

1
Department of Anesthesia, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
2
Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
3
Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
4
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
5
Division of Bioinformatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

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).

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01140724 NCT01839461.

PMID:
26810133
PMCID:
PMC4959996
[Available on 2017-09-01]
DOI:
10.1038/tpj.2015.98
[Indexed for MEDLINE]
Free PMC Article

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