Evaluation of analytical and clinical performance of a dual-probe phenotyping method for CYP2D6 polymorphism and CYP3A4 activity screening.
Ther Drug Monit
; 22(4): 486-96, 2000 Aug.
Article
en En
| MEDLINE
| ID: mdl-10942192
ABSTRACT
A bioanalytical method for the determination of dextromethorphan (DEX) and its metabolites dextrorphan (DTX), 3-methoxymorphinan (3MM), and 3-hydroxymorphinan (3HM) in human urine was developed for CYP2D6 phenotyping and CYP3A4 activity measurements in clinical pharmacology studies using dextromethorphan administered in a drinking solution as substrate. The method was evaluated by thorough conventional validation and by a cross-validation of the method with a previously applied method for dextromethorphan and dextrorphan only (CYP2D6 phenotyping). Cross-validation with the former method showed no significant differences in measured concentrations of volunteer samples. This guaranteed the consistency of epidemiologic data in the database collected from two methods. For the CYP2D6 and CYP3A4 evaluations, the clinical parameters are ratios of concentrations. It appeared that severe variance in individual concentrations generally did not influence the variance of ratios significantly, because experimental errors in concentrations of two analytes proved to correlate considerably. For CYP2D6 values around the antimodes, the chance of a misclassification is very small. The chance of classifying an extensive metabolizer as a poor metabolizer or vice versa is negligible. For CYP3A4 activity determinations it was concluded that in general a change in dextromethorphan/3-methoxymorphinan (DEX/3MM) ratios of 10% or more as detected with the current method, is a significant increase or decrease in the activity of CYP3A4. The authors concluded that they had obtained an analytically valid and clinically reliable bioanalytical method for the determination of dextromethorphan and its metabolites dextrorphan, 3-methoxymorphinan, and 3-hydroxymorphinan in human urine for CYP2D6 phenotyping and CYP3A4 activity measurements for clinical pharmacology studies.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Polimorfismo Genético
/
Citocromo P-450 CYP2D6
/
Sistema Enzimático del Citocromo P-450
/
Oxigenasas de Función Mixta
Tipo de estudio:
Diagnostic_studies
/
Evaluation_studies
/
Screening_studies
Límite:
Humans
Idioma:
En
Revista:
Ther Drug Monit
Año:
2000
Tipo del documento:
Article
País de afiliación:
Países Bajos