The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone.
OBJECTIVE
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.


METHODS
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 x 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.


RESULTS
CYP2D6 activity was correlated with oxymorphone and noroxymorphone AUCs and C(max) (-0.71 < Spearman correlation coefficient rhos < -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(infinity) by 70%. Blocking CYP3A4 (with ketoconazole) tripled oxymorphone AUC(infinity) and reduced noroxycodone and noroxymorphone AUCs by 80%. Shunting to CYP2D6 pathway was observed after CYP3A4 inhibition.


CONCLUSIONS
Drug-drug interactions via CYP2D6 and CYP3A affected oxycodone pharmacokinetics and its magnitude depended on CYP2D6 genotype.
Samer
C F
CF
Clinical Pharmacology and Toxicology and Multidisciplinary Pain Centre, Department of Anaesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Switzerland. Caroline.Samer@hcuge.ch
Daali
Y
Y
Wagner
M
M
Hopfgartner
G
G
Eap
C B
CB
Rebsamen
M C
MC
Rossier
M F
MF
Hochstrasser
D
D
Dayer
P
P
Desmeules
J A
JA
D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D050216:Metabolic Detoxication, Phase I / Q000235:genetics; D010098:Oxycodone / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011802:Quinidine / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000378:metabolism; D055815:Young Adult
D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D017450:Receptors, Opioid, mu; D010098:Oxycodone; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D011802:Quinidine; D007654:Ketoconazole