Measurement of CYP2D6 and CYP3A4 activity in vivo with dextromethorphan: sources of variability and predictors of adverse effects in 419 healthy subjects.
OBJECTIVE
Dextromethorphan (DEM) shares part of the adverse event profile of opioids and is widely used as a probe drug for CYP2D6 phenotyping and for the assessment of CYP2D6 activity. It has also been used to assess CYP3A4 activity. This study examined the influence of anthropometric variables, oral contraceptives, smoking habits, mu-opioid receptor and MDR1 genetic polymorphisms and components of the DEM ratios on the variability of CYP2D6 and CYP3A4 metabolic ratios and on the occurrence of adverse events following DEM administration.


METHODS
This was a retrospective analysis of a database in 419 healthy subjects. CYP2D6 and CYP3A4 metabolic ratios were measured as the log of the ratios of the amount of DEM to the amount of dextrorphan (DOR) and of the amount of DEM to the amount of 3-methoxy-morphinan (MET) excreted in urine during a 12-h time period, respectively, following the oral administration of 80 mg of dextromethorphan hydrobromide. Logistic regression was performed to examine the factors associated with changes in metabolic ratios and with the occurrence of adverse events.


RESULTS
The CYP2D6 metabolic ratio allowed identification of extensive and poor metabolizers of DEM. The CYP2D6 and CYP3A4 metabolic ratios were not strictly independent one from each other. Based on multivariate analysis, the CYP2D6 metabolic ratio was a stronger independent predictor of adverse events (p<0.0001) than the CYP2D6 phenotype (p=0.05). Anthropometric variables, oral contraceptives, smoking habits, mu-opioid receptor and MDR1 genetic polymorphisms did not significantly contribute to changes in metabolic ratios or to the occurrence of adverse events.


CONCLUSIONS
Dextromethorphan can be used for CYP2D6 phenotyping, but the CYP2D6 and CYP3A4 metabolic ratios are not strictly independent one from each other. The CYP2D6 metabolic ratio predicts adverse events to DEM as does CYP2D6 phenotype, and extensive metabolizer subjects are not protected against adverse events.
Funck-Brentano
Christian
C
INSERM--AP-HP, Clinical Investigation Center, CIC-9304, and Department of Pharmacology, Pierre et Marie Curie University, 75012 Paris, France. christian.funck-brentano@sat.aphp.fr
Boëlle
Pierre-Yves
PY
Verstuyft
Céline
C
Bornert
Célia
C
Becquemont
Laurent
L
Poirier
Jean-Marie
JM
D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003915:Dextromethorphan / Q000009:adverse effects* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D012189:Retrospective Studies
D000701:Analgesics, Opioid; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human