Dextromethorphan as an in vivo probe for the simultaneous determination of CYP2D6 and CYP3A activity.
Dextromethorphan (DM) is O-demethylated into dextrorphan (DEX) in humans by the cytochrome P450 designated as CYP2D6 and N-demethylated into 3-methoxymorphinan (3MM) via CYP3As. Clinically, DM has been successfully used as an index of CYP2D6 and this paper describes analytical and clinical data that will help evaluate the use of DM hydrobromide as a probe of CYP3A activity. DM and its three demethylated metabolites were measured in a 4-h spot urine sample using a HPLC method employing solid-phase extraction (C(18)), analysis on a phenyl column [mobile phase, methanol-acetonitrile-phosphate buffer (10 mM, pH 3.5, 20:25:55, v/v)] and fluorescence detection (excitation at lambda=228 nm, no emission cut-off filter). The urinary molar ratio DM-DEX was used to assess CYP2D6 activity while DM-3MM was used for CYP3As. The DM-3MM ratios were sensitive to the co-administration of selective CYP3A inhibitors grapefruit juice and erythromycin. In addition, in healthy volunteers and cancer patients, the N-demethylation of DM correlated with the CYP3A-mediated metabolism of verapamil and tamoxifen. DM appears to be a promising way to simultaneously phenotype patients for CYP2D6 and CYP3As.
Ducharme
J
J
Department of Oncology, McGill University, Montreal General Hospital, Quebec, Canada.
Abdullah
S
S
Wainer
I W
IW
D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism / Q000652:urine*; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D015335:Molecular Probes; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010641:Phenotype; D015203:Reproducibility of Results; D013050:Spectrometry, Fluorescence; D013629:Tamoxifen / Q000378:metabolism / Q000627:therapeutic use; D014700:Verapamil / Q000378:metabolism / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D015335:Molecular Probes; D013629:Tamoxifen; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating