Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

The Pharmacogenomics Journal volume 17, pages 162–169 (2017)Cite this article

Subjects

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).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Lotsch J, Dudziak R, Freynhagen R, Marschner J, Geisslinger G . Fatal respiratory depression after multiple intravenous morphine injections. Clin Pharmacokinet 2006; 45: 1051–1060.

    PubMed  Google Scholar 

  2. Nelson KL, Yaster M, Kost-Byerly S, Monitto CL . A national survey of American Pediatric Anesthesiologists: patient-controlled analgesia and other intravenous opioid therapies in pediatric acute pain management. Anesth Analg 2010; 110: 754–760.

    CAS  PubMed  Google Scholar 

  3. Fecho K, Lunney AT, Boysen PG, Rock P, Norfleet EA . Postoperative mortality after inpatient surgery: incidence and risk factors. Ther Clin Risk Manag 2008; 4: 681–688.

    PubMed  PubMed Central  Google Scholar 

  4. Fecho K, Jackson F, Smith F, Overdyk FJ . In-hospital resuscitation: opioids and other factors influencing survival. Ther Clin Risk Manag 2009; 5: 961–968.

    PubMed  PubMed Central  Google Scholar 

  5. Angst MS, Lazzeroni LC, Phillips NG, Drover DR, Tingle M, Ray A et al. Aversive and reinforcing opioid effects: a pharmacogenomic twin study. Anesthesiology 2012; 117: 22–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Chidambaran V, Mavi J, Esslinger H, Pilipenko V, Martin LJ, Zhang K et al. Association of OPRM1 A118G variant with risk of morphine-induced respiratory depression following spine fusion in adolescents. Pharmacogenomics J 2014; 15: 255–262.

    PubMed  PubMed Central  Google Scholar 

  7. Sadhasivam S, Chidambaran V, Zhang X, Meller J, Esslinger H, Zhang K et al. Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics. Pharmacogenomics J 2014; 15: 119–126.

    PubMed  Google Scholar 

  8. Sadhasivam S, Zhang X, Chidambaran V, Mavi J, Pilipenko V, Mersha TB et al. Novel associations between FAAH genetic variants and postoperative central opioid-related adverse effects. Pharmacogenomics J 2015; 15: 436–442.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Klepstad P, Dale O, Kaasa S, Zahlsen K, Aamo T, Fayers P et al. Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: a prospective survey in 300 adult cancer patients. Acta Anaesthesiol Scand 2003; 47: 725–731.

    CAS  PubMed  Google Scholar 

  10. Thorn CF, Klein TE, Altman RB . Codeine and morphine pathway. Pharmacogenet Genomics 2009; 19: 556–558.

    CAS  PubMed  Google Scholar 

  11. Grisk O, Schlueter T, Steinbach A, Ciecholewski S, Kloeting I, Voelker U et al. Effects of generalized and kidney specific Mrp2 (ABCC2) deficiency on renal elimination of PAH and morphine-6-glucuronide. FASEB J 2007; 21: 11.

    Google Scholar 

  12. Huwyler J, Drewe J, Klusemann C, Fricker G . Evidence for P-glycoprotein-modulated penetration of morphine-6-glucuronide into brain capillary endothelium. Br J Pharmacol 1996; 118: 1879–1885.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kharasch ED, Hoffer C, Whittington D, Sheffels P . Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol Ther 2003; 74: 543–554.

    CAS  PubMed  Google Scholar 

  14. Lotsch J, Schmidt R, Vetter G, Schmidt H, Niederberger E, Geisslinger G et al. Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoprotein. J Neurochem 2002; 83: 241–248.

    CAS  PubMed  Google Scholar 

  15. Tzvetkov MV, dos Santos Pereira JN, Meineke I, Saadatmand AR, Stingl JC, Brockmöller J . Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. Biochem Pharmacol 2013; 86: 666–678.

    CAS  PubMed  Google Scholar 

  16. van de Wetering K, Zelcer N, Kuil A, Feddema W, Hillebrand M, Vlaming ML et al. Multidrug resistance proteins 2 and 3 provide alternative routes for hepatic excretion of morphine-glucuronides. Mol Pharmacol 2007; 72: 387–394.

    CAS  PubMed  Google Scholar 

  17. Xie R, Hammarlund-Udenaes M, de Boer AG, de Lange EC . The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice. Br J Pharmacol 1999; 128: 563–568.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Zelcer N, van de Wetering K, Hillebrand M, Sarton E, Kuil A, Wielinga PR et al. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc Natl Acad Sci USA 2005; 102: 7274–7279.

    CAS  PubMed  Google Scholar 

  19. Venkatasubramanian R, Fukuda T, Niu J, Mizuno T, Chidambaran V, Vinks AA et al. ABCC3 and OCT1 genotypes influence pharmacokinetics of morphine in children. Pharmacogenomics 2014; 15: 1297–1309.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Fukuda T, Chidambaran V, Mizuno T, Venkatasubramanian R, Ngamprasertwong P, Olbrecht V et al. OCT1 genetic variants influence the pharmacokinetics of morphine in children. Pharmacogenomics 2013; 14: 1141–1151.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chervin RD, Hedger K, Dillon JE, Pituch KJ . Pediatric sleep questionnaire (PSQ): validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Sleep Med 2000; 1: 21–32.

    CAS  PubMed  Google Scholar 

  22. Chervin RD, Weatherly RA, Garetz SL, Ruzicka DL, Giordani BJ, Hodges EK et al. Pediatric sleep questionnaire: prediction of sleep apnea and outcomes. Arch Otolaryngol Head Neck Surg 2007; 133: 216–222.

    PubMed  Google Scholar 

  23. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 2012; 22: 1790–1797.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Clavijo CF, Hoffman KL, Thomas JJ, Carvalho B, Chu LF, Drover DR et al. A sensitive assay for the quantification of morphine and its active metabolites in human plasma and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 2011; 400: 715–728.

    CAS  PubMed  Google Scholar 

  25. Lindbom L, Pihlgren P, Jonsson EN . PsN-Toolkit-a collection of computer intensive statistical methods for non-linear mixed effect modeling using NON MEM. Comput Methods Programs Biomed 2005; 79: 241–257.

    PubMed  Google Scholar 

  26. Uchiumi T, Hinoshita E, Haga S, Nakamura T, Tanaka T, Toh S et al. Isolation of a novel human canalicular multispecific organic anion transporter, cMOAT2/MRP3, and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport. Biochem Biophys Res Commun 1998; 252: 103–110.

    CAS  PubMed  Google Scholar 

  27. Konig J, Rost D, Cui Y, Keppler D . Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology 1999; 29: 1156–1163.

    CAS  PubMed  Google Scholar 

  28. Borst P, Elferink RO . Mammalian ABC transporters in health and disease. Annu Rev Biochem 2002; 71: 537–592.

    CAS  PubMed  Google Scholar 

  29. Kruh GD, Belinsky MG . The MRP family of drug efflux pumps. Oncogene 2003; 22: 7537–7552.

    CAS  PubMed  Google Scholar 

  30. Zelcer N, van de Wetering K, de Waart R, Scheffer GL, Marschall HU, Wielinga PR et al. Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides. J Hepatol 2006; 44: 768–775.

    CAS  PubMed  Google Scholar 

  31. Milne RW, Jensen RH, Larsen C, Evans AM, Nation RL . Comparison of the disposition of hepatically-generated morphine-3-glucuronide and morphine-6-glucuronide in isolated perfused liver from the guinea pig. Pharm Res 1997; 14: 1014–1018.

    CAS  PubMed  Google Scholar 

  32. McVicker G, van de Geijn B, Degner JF, Cain CE, Banovich NE, Raj A et al. Identification of genetic variants that affect histone modifications in human cells. Science 2013; 342: 747–749.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Schaub MA, Boyle AP, Kundaje A, Batzoglou S, Snyder M . Linking disease associations with regulatory information in the human genome. Genome Res 2012; 22: 1748–1759.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Heintzman ND, Ren B . Finding distal regulatory elements in the human genome. Curr Opin Genet Dev 2009; 19: 541–549.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Visel A, Rubin EM, Pennacchio LA . Genomic views of distant-acting enhancers. Nature 2009; 461: 199–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 2009; 459: 108–112.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z et al. High-resolution profiling of histone methylations in the human genome. Cell 2007; 129: 823–837.

    CAS  Google Scholar 

  38. Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA 2010; 107: 21931–21936.

    CAS  PubMed  Google Scholar 

  39. Christrup LL . Morphine metabolites. Acta Anaesthesiol Scand 1997; 41: 116–122.

    CAS  PubMed  Google Scholar 

  40. Hasselstrom J, Sawe J . Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharm 1993; 24: 344–354.

    CAS  Google Scholar 

  41. Lang T, Hitzl M, Burk O, Mornhinweg E, Keil A, Kerb R et al. Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver. Pharmacogenetics 2004; 14: 155–164.

    CAS  PubMed  Google Scholar 

  42. Gradhand U, Tegude H, Burk O, Eichelbaum M, Fromm MF, Konig J . Functional analysis of the polymorphism -211C>T in the regulatory region of the human ABCC3 gene. Life Sci 2007; 80: 1490–1494.

    CAS  PubMed  Google Scholar 

  43. Doerfel C, Rump A, Sauerbrey A, Gruhn B, Zintl F, Steinbach D . In acute leukemia, the polymorphism -211C>T in the promoter region of the multidrug resistance-associated protein 3 (MRP3) does not determine the expression level of the gene. Pharmacogenet Genomics 2006; 16: 149–150.

    CAS  PubMed  Google Scholar 

  44. Sawe J, Svensson JO, Rane A . Morphine metabolism in cancer patients on increasing oral doses—no evidence for autoinduction or dose-dependence. Br J Clin Pharmacol 1983; 16: 85–93.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by USPHS Grant #UL1 RR026314 from the National Center for Research Resources and Electronic Medical Records and Genomics (eMERGE) network U01 grant #U01HG006828, NIH and with the Place Outcomes Research Award (PI: SS) and Translational Research Award (PIs: SS), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. The study in the spine surgical cohort was supported by Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under award number K23HD082782 (PI: VC), and the Clinical Research Feasibility Funds (PI: VC) via Grant 8 UL1 TR000077 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. It was also supported by the APSF/ASA Safety Scientist Career Development Award by the Anesthesia Patient Safety Foundation (PI: Chidambaran). Additional research funding support was provided by the Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. No financial support except departmental salary support for the authors. This pharmacogenetic study was designed and undertaken by the authors.

Author contributions

The authors directed and had access to all the analyses and the full clinical and genetic database, wrote all drafts of the report, decided to publish the results and attest for the accuracy and completeness of the data. Specifically, SS, VC and TF conceived of and designed the research. SS, VC, RV, JN and TM acquired the data. SS, VC, RV, AAV, XZ and LJM analyzed and interpreted the data. XZ and JM did localization of SNPs in ABCC3 transporter and proposed mechanistic pathways. XZ and LJM did statistical analyses. VC, RV and SS drafted the initial manuscript. SS participated in funding and supervision. All authors made critical revisions to the report for important intellectual content.

Author information

Authors and Affiliations

  1. Department of Anesthesia, College of Medicine, University of Cincinnati, Cincinnati,, OH, USA

    V Chidambaran, R Venkatasubramanian, J Niu & S Sadhasivam

  2. Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati,, OH, USA

    V Chidambaran, T Fukuda, J Meller, A A Vinks & S Sadhasivam

  3. Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati,, OH, USA

    R Venkatasubramanian, J Niu, T Mizuno, T Fukuda & A A Vinks

  4. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati,, OH, USA

    X Zhang & L J Martin

  5. Division of Bioinformatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    J Meller

Authors
  1. V Chidambaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Venkatasubramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L J Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Mizuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Meller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A A Vinks
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Sadhasivam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Sadhasivam.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chidambaran, V., Venkatasubramanian, R., Zhang, X. et al. ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children. Pharmacogenomics J 17, 162–169 (2017). https://doi.org/10.1038/tpj.2015.98

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.98

This article is cited by

Search

Advanced search

Quick links