CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients

Rajiv Balyan, Marc Mecoli, Raja Venkatasubramanian, Vidya Chidambaran, Nichole Kamos, Smokey Clay, David L. Moore, Jagroop Mavi, Chris D. Glover, Peter Szmuk, Alexander Vinks, Senthilkumar Sadhasivam

Research output: Contribution to journalArticle

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Abstract

Aim: Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects oxymorphone formation. This study aimed to associate CYP2D6 genotype and oxycodone's metabolism. Methods: 30 children were administered oral oxycodone postoperatively. Plasma levels of oxycodone and oxymorphone, and CYP2D6 genotype were analyzed. CYP2D6 genotype and oxycodone metabolism phenotype were determined based on CYP2D6 total activity score (TAS) and metabolism phenotype: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) or ultrarapid metabolizer (UM). Results: Compared with PM/IM subjects, significantly greater oxymorphone exposure was seen in EM subjects (p = 0.02 for Cmax, p = 0.016 for AUC0-6 and p = 0.026 for AUC0-24). Similarly, higher TAS value was found to be associated with greater oxymorphone exposure. Higher conversion of oxycodone to oxymorphone was observed in EM subjects compared with PM/IM subjects (p = 0.0007 for Cmax, p = 0.001 for AUC0-6 and p = 0.004 for AUC0-24). Conclusion: CYP2D6 phenotypes explain metabolism of oxycodone in children, and oxymorphone exposure is higher in CYP2D6 EM phenotype. Further studies are needed to predict the occurrence of adverse event and tailor oxycodone dose for a specific CYP2D6 phenotype.

Original languageEnglish (US)
Pages (from-to)337-348
Number of pages12
JournalPharmacogenomics
Volume18
Issue number4
DOIs
StatePublished - Mar 1 2017

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Oxycodone
Cytochrome P-450 CYP2D6
Oxymorphone
Pharmacogenetics
Pharmacokinetics
Pediatrics
Phenotype
Genotype
Liver

Keywords

  • CYP2D6
  • oxycodone
  • pediatrics
  • pharmacogenetics
  • pharmacokinetics
  • surgical pain

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Balyan, R., Mecoli, M., Venkatasubramanian, R., Chidambaran, V., Kamos, N., Clay, S., ... Sadhasivam, S. (2017). CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients. Pharmacogenomics, 18(4), 337-348. https://doi.org/10.2217/pgs-2016-0183

CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients. / Balyan, Rajiv; Mecoli, Marc; Venkatasubramanian, Raja; Chidambaran, Vidya; Kamos, Nichole; Clay, Smokey; Moore, David L.; Mavi, Jagroop; Glover, Chris D.; Szmuk, Peter; Vinks, Alexander; Sadhasivam, Senthilkumar.

In: Pharmacogenomics, Vol. 18, No. 4, 01.03.2017, p. 337-348.

Research output: Contribution to journalArticle

Balyan, R, Mecoli, M, Venkatasubramanian, R, Chidambaran, V, Kamos, N, Clay, S, Moore, DL, Mavi, J, Glover, CD, Szmuk, P, Vinks, A & Sadhasivam, S 2017, 'CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients', Pharmacogenomics, vol. 18, no. 4, pp. 337-348. https://doi.org/10.2217/pgs-2016-0183
Balyan R, Mecoli M, Venkatasubramanian R, Chidambaran V, Kamos N, Clay S et al. CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients. Pharmacogenomics. 2017 Mar 1;18(4):337-348. https://doi.org/10.2217/pgs-2016-0183
Balyan, Rajiv ; Mecoli, Marc ; Venkatasubramanian, Raja ; Chidambaran, Vidya ; Kamos, Nichole ; Clay, Smokey ; Moore, David L. ; Mavi, Jagroop ; Glover, Chris D. ; Szmuk, Peter ; Vinks, Alexander ; Sadhasivam, Senthilkumar. / CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients. In: Pharmacogenomics. 2017 ; Vol. 18, No. 4. pp. 337-348.
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abstract = "Aim: Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects oxymorphone formation. This study aimed to associate CYP2D6 genotype and oxycodone's metabolism. Methods: 30 children were administered oral oxycodone postoperatively. Plasma levels of oxycodone and oxymorphone, and CYP2D6 genotype were analyzed. CYP2D6 genotype and oxycodone metabolism phenotype were determined based on CYP2D6 total activity score (TAS) and metabolism phenotype: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) or ultrarapid metabolizer (UM). Results: Compared with PM/IM subjects, significantly greater oxymorphone exposure was seen in EM subjects (p = 0.02 for Cmax, p = 0.016 for AUC0-6 and p = 0.026 for AUC0-24). Similarly, higher TAS value was found to be associated with greater oxymorphone exposure. Higher conversion of oxycodone to oxymorphone was observed in EM subjects compared with PM/IM subjects (p = 0.0007 for Cmax, p = 0.001 for AUC0-6 and p = 0.004 for AUC0-24). Conclusion: CYP2D6 phenotypes explain metabolism of oxycodone in children, and oxymorphone exposure is higher in CYP2D6 EM phenotype. Further studies are needed to predict the occurrence of adverse event and tailor oxycodone dose for a specific CYP2D6 phenotype.",
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AU - Mecoli, Marc

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AU - Kamos, Nichole

AU - Clay, Smokey

AU - Moore, David L.

AU - Mavi, Jagroop

AU - Glover, Chris D.

AU - Szmuk, Peter

AU - Vinks, Alexander

AU - Sadhasivam, Senthilkumar

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AB - Aim: Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects oxymorphone formation. This study aimed to associate CYP2D6 genotype and oxycodone's metabolism. Methods: 30 children were administered oral oxycodone postoperatively. Plasma levels of oxycodone and oxymorphone, and CYP2D6 genotype were analyzed. CYP2D6 genotype and oxycodone metabolism phenotype were determined based on CYP2D6 total activity score (TAS) and metabolism phenotype: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) or ultrarapid metabolizer (UM). Results: Compared with PM/IM subjects, significantly greater oxymorphone exposure was seen in EM subjects (p = 0.02 for Cmax, p = 0.016 for AUC0-6 and p = 0.026 for AUC0-24). Similarly, higher TAS value was found to be associated with greater oxymorphone exposure. Higher conversion of oxycodone to oxymorphone was observed in EM subjects compared with PM/IM subjects (p = 0.0007 for Cmax, p = 0.001 for AUC0-6 and p = 0.004 for AUC0-24). Conclusion: CYP2D6 phenotypes explain metabolism of oxycodone in children, and oxymorphone exposure is higher in CYP2D6 EM phenotype. Further studies are needed to predict the occurrence of adverse event and tailor oxycodone dose for a specific CYP2D6 phenotype.

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