Rajiv Balyan1,2, Marc Mecoli1,3, Raja Venkatasubramanian1,2, Vidya Chidambaran1,3, Nichole Kamos3, Smokey Clay1,3, David L Moore1,3, Jagroop Mavi1,3, Chris D Glover4, Peter Szmuk5,6, Alexander Vinks2,3, Senthilkumar Sadhasivam1,3. 1. Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA. 2. Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. 3. Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA. 4. Department of Anesthesia, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. 5. Department of Anesthesiology & Pain Management, University of Texas Southwestern & Children's Medical Center, Dallas, TX 75390, USA. 6. Outcome Research Consortium, Cleveland, OH 44195, USA.
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.
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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