title: CYP2D6 genotype dependent oxycodone metabolism in postoperative patients.
abstract: BACKGROUND
  The impact of polymorphic cytochrome P450 CYP2D6 enzyme on oxycodone's metabolism and clinical efficacy is currently being discussed. However, there are only spare data from postoperative settings. The hypothesis of this study is that genotype dependent CYP2D6 activity influences plasma concentrations of oxycodone and its metabolites and impacts analgesic consumption.
  
  
  METHODS
  Patients received oxycodone 0.05 mg/kg before emerging from anesthesia and patient-controlled analgesia (PCA) for the subsequent 48 postoperative hours. Blood samples were drawn at 30, 90 and 180 minutes after the initial oxycodone dose. Plasma concentrations of oxycodone and its metabolites oxymorphone, noroxycodone and noroxymorphone were analyzed by liquid chromatography-mass spectrometry with electrospray ionization. CYP2D6 genotyping was performed and 121 patients were allocated to the following genotype groups: PM (poor metabolizer: no functionally active CYP2D6 allele), HZ/IM (heterozygous subjects, intermediate metabolizers with decreased CYP2D6 activity), EM (extensive metabolizers, normal CYP2D6 activity) and UM (ultrarapid metabolizers, increased CYP2D6 activity). Primary endpoint was the genotype dependent metabolite ratio of plasma concentrations oxymorphone/oxycodone. Secondary endpoint was the genotype dependent analgesic consumption with calculation of equianalgesic doses compared to the standard non-CYP dependent opioid piritramide.
  
  
  RESULTS
  Metabolism differed between CYP2D6 genotypes. Mean (95%-CI) oxymophone/oxycodone ratios were 0.10 (0.02/0.19), 0.13 (0.11/0.16), 0.18 (0.16/0.20) and 0.28 (0.07/0.49) in PM, HZ/IM, EM and UM, respectively (p = 0.005). Oxycodone consumption up to the 12(th) hour was highest in PM (p = 0.005), resulting in lowest equianalgesic doses of piritramide versus oxycodone for PM (1.6 (1.4/1.8); EM and UM 2.2 (2.1/2.3); p<0.001). Pain scores did not differ between genotypes.
  
  
  CONCLUSIONS
  In this postoperative setting, the number of functionally active CYP2D6 alleles had an impact on oxycodone metabolism. The genotype also impacted analgesic consumption, thereby causing variation of equianalgesic doses piritramide : oxycodone. Different analgesic needs by genotypes were met by PCA technology in this postoperative cohort.
authors.affiliation: Department of Anaesthesiology and Pain Medicine, Inselspital, University of Bern, Bern, Switzerland. ulrike.stamer@dkf.unibe.ch
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Stamer
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Malte
authors.initials: M
authors.lastname: Book
authors.forename: Lutz E
authors.initials: LE
authors.lastname: Lehmann
authors.forename: Frank
authors.initials: F
authors.lastname: Stuber
authors.forename: Frank
authors.initials: F
authors.lastname: Musshoff
mesh_terms: D000368:Aged; D000701:Analgesics, Opioid / Q000097:blood / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009019:Morphinans / Q000097:blood / Q000378:metabolism; D010098:Oxycodone / Q000097:blood / Q000378:metabolism*; D010111:Oxymorphone / Q000097:blood / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000701:Analgesics, Opioid; D009019:Morphinans; C077256:noroxycodone; C526569:noroxymorphone; D010111:Oxymorphone; D010098:Oxycodone; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A
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