Dextromethorphan as an in vivo probe for the simultaneous determination of CYP2D6 and CYP3A activity |
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| Affiliation: | 1. Department of Emergency, Clermont-Ferrand University Hospital, Clermont-Ferrand, France;2. University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Vascular Medicine, Groningen, Netherlands;3. Department of Internal Medicine, Tergooi Hilversum, Netherlands and Department of Vascular Medicine, University Medical Center Groningen, Groningen, Netherlands;4. Department of Internal Medicine, Hospital Municipal de Badalona, Barcelona, Spain;5. Department of Internal Medicine, Hospital Reina Sofía, Tudela, Navarra, Spain;6. Department of Pneumonology, Complejo Hospitalario de Navarra, Pamplona, Spain;7. Department of Medicina d''Urgenza, Ospedale San Camilo, Rome, Italy;8. Department of Internal Medicine, Hospital Vall d''Hebrón, Barcelona, Spain;9. Department of Internal Medicine, Hospital Universitario Reina Sofía, Córdoba, Spain;10. Thrombosis Research Group, Université de Saint-Etienne, Jean Monnet, Inserm, Service de Médecine Interne et Thérapeutique, Hôpital Nord, Saint-Etienne, France;11. Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol de Badalona, Barcelona, Universidad Católica de Murcia, Spain;1. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA;2. Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, FL, USA;3. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA |
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| Abstract: | 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 (C18), 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 λ=228 nm, no emmission 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. |
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