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The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone
Author(s) -
Samer CF,
Daali Y,
Wagner M,
Hopfgartner G,
Eap CB,
Rebsamen MC,
Rossier MF,
Hochstrasser D,
Dayer P,
Desmeules JA
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00673.x
Subject(s) - oxymorphone , oxycodone , pharmacology , pharmacokinetics , dextromethorphan , quinidine , cyp2d6 , cyp3a , triazolam , crossover study , pharmacodynamics , drug interaction , placebo , medicine , chemistry , opioid , cytochrome p450 , benzodiazepine , receptor , pathology , metabolism , alternative medicine
Background and purpose: There is high interindividual variability in the activity of drug‐metabolizing enzymes catalysing the oxidation of oxycodone [cytochrome P450 (CYP) 2D6 and 3A], due to genetic polymorphisms and/or drug–drug interactions. The effects of CYP2D6 and/or CYP3A activity modulation on the pharmacokinetics of oxycodone remains poorly explored. Experimental approach: A randomized crossover double‐blind placebo‐controlled study was performed with 10 healthy volunteers genotyped for CYP2D6 [six extensive (EM), two deficient (PM/IM) and two ultrarapid metabolizers (UM)]. The volunteers randomly received on five different occasions: oxycodone 0.2 mg·kg −1 and placebo; oxycodone and quinidine (CYP2D6 inhibitor); oxycodone and ketoconazole (CYP3A inhibitor); oxycodone and quinidine+ketoconazole; placebo. Blood samples for plasma concentrations of oxycodone and metabolites (oxymorphone, noroxycodone and noroxymorphone) were collected for 24 h after dosing. Phenotyping for CYP2D6 (with dextromethorphan) and CYP3A (with midazolam) were assessed at each session. Key results: CYP2D6 activity was correlated with oxymorphone and noroxymorphone AUCs and C max (−0.71 < Spearman correlation coefficient ρs < −0.92). Oxymorphone C max was 62% and 75% lower in PM than EM and UM. Noroxymorphone C max reduction was even more pronounced (90%). In UM, oxymorphone and noroxymorphone concentrations increased whereas noroxycodone exposure was halved. Blocking CYP2D6 (with quinidine) reduced oxymorphone and noroxymorphone C max by 40% and 80%, and increased noroxycodone AUC ∞ by 70%. Blocking CYP3A4 (with ketoconazole) tripled oxymorphone AUC ∞ and reduced noroxycodone and noroxymorphone AUCs by 80%. Shunting to CYP2D6 pathway was observed after CYP3A4 inhibition. Conclusions and implications: Drug–drug interactions via CYP2D6 and CYP3A affected oxycodone pharmacokinetics and its magnitude depended on CYP2D6 genotype.