Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication.
Codeine is an analgesic drug acting on mu-opiate receptors predominantly via its metabolite morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Whereas it is known that individuals lacking CYP2D6 activity (poor metabolizers, PM) suffer from poor analgesia from codeine, ultra-fast metabolizers (UM) due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects and no systematical study has been performed so far on this question. A single dose of 30 mg codeine was administered to 12 UM of CYP2D6 substrates carrying a CYP2D6 gene duplication, 11 extensive metabolizers (EM) and three PM. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism methods and a single-base primer extension method for characterization of the gene-duplication alleles. Pharmacokinetics was measured over 24 h after drug intake and codeine and its metabolites in plasma and urine were analyzed by liquid chromatography with tandem mass spectrometry. Significant differences between the EM and UM groups were detected in areas under the plasma concentration versus time curves (AUCs) of morphine with a median (range) AUC of 11 (5-17) microg h l(-1) in EMs and 16 (10-24) microg h l(-1) in UM (P=0.02). In urine collected over 12 h, the metabolic ratios of the codeine+codeine-6-glucuronide divided by the sum of morphine+its glucuronides metabolites were 11 (6-17) in EMs and 9 (6-16) in UM (P=0.05). Ten of the 11 CYP2D6 UMs felt sedation (91%) compared to six (50%) of the 12 EMs (P=0.03). CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM. No severe adverse effects were seen in the UMs in our study most likely because we used for safety reasons a low dose of only 30 mg. It might be good if physicians would know about the CYP2D6 duplication genotype of their patients before administering codeine.
Kirchheiner
J
J
Department of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Ulm, Germany. julia.kirchheiner@uni-ulm.de
Schmidt
H
H
Tzvetkov
M
M
Keulen
J-T H A
JT
Lötsch
J
J
Roots
I
I
Brockmöller
J
J
D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D003061:Codeine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D003243:Consciousness / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D003640:Dealkylation; D020440:Gene Duplication; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000009:adverse effects / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000493:pharmacokinetics; D010641:Phenotype; D012016:Reference Values
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C061773:codeine-6-glucuronide; D019389:Cytochrome P-450 CYP2D6; C018108:morphine-3-glucuronide; D003061:Codeine