Micro-cocktail validation for CYP3A and CYP2D6 assessment using a low dose of midazolam (0.075 mg) and dextromethorphan (2.5 mg)

Détails

ID Serval
serval:BIB_B5827BA589B8
Type
Actes de conférence (partie): contribution originale à la littérature scientifique, publiée à l'occasion de conférences scientifiques, dans un ouvrage de compte-rendu (proceedings), ou dans l'édition spéciale d'un journal reconnu (conference proceedings).
Sous-type
Abstract (résumé de présentation): article court qui reprend les éléments essentiels présentés à l'occasion d'une conférence scientifique dans un poster ou lors d'une intervention orale.
Collection
Publications
Institution
Titre
Micro-cocktail validation for CYP3A and CYP2D6 assessment using a low dose of midazolam (0.075 mg) and dextromethorphan (2.5 mg)
Auteur(s)
Daali Youssef, Samer C., Eap Chin-Bin, Rebsamen Michaëla, Rossier Michel, Dayer Pierre, Desmeules Jules
ISBN
0009-9236
Statut éditorial
Publié
Date de publication
2007
Peer-reviewed
Oui
Volume
81
Série
Clinical Pharmacology and Therapeutics
Pages
S77-S77
Langue
anglais
Notes
SAPHIRID:61456
Résumé
BACKGROUND/AIM: Cocktail approach is generally preferred to individual administration of probes in order to characterize the activity of multiple enzymes. However, cocktail strategy has several drawbacks such as probes interactions, tolerability or toxicity. Hence, there is a need to develop cocktails using low doses. Our aim was to investigate whether the simultaneous oral administration of microdoses of midazolam (MDZ) and dextromethorphan (DEM) can be used to assess the simultaneous activities of CYP3A and CYP2D6.
METHODS: As part of a 5 arm randomized cross-over control trial on the analgesic efficacy of oxycodone, ten healthy young non-smoking males received the following combinations of drugs: Quinidine (Q) þ ketoconazole (K) or Q þ placebo (P) or K þ P or P þ P. In all cases MDZ (0.075 mg) and DEM (2.5 mg) were administrated 1 hour after Q, K or P. CYP2D6 and CYP3A activities were determined after urine collection during 8 hours (ratio DEM/ DOR), and a blood sample (EDTA) after 30 min (ratio 1-OH-MDZ/ MDZ). DEM and DOR analysis was performed using LC-fluorescence. MDZ and 1-OH-MDZ determination was performed using GC-MS. Allele's variants of CYP2D6 were detected using the AmpliChipTM.
RESULTS: CYP2D6 genotype predicted 1 poor (PM), 1 intermediate (IM), 7 extensive (EM) and 2 ultra rapid (UM) metabolizers. A good correlation was obtained between the predicted and the measured phenotypes except for 1 EM phenotyped as UM. Two duplications for alleles *41/*41xN and *1/*2xN were detected and the two volunteers were phenotyped as UM. A potent inhibition of CYP2D6 or CYP3A4 was obtained when Q or K was used. Mean metabolic ratio DEM/DOR in P and K groups were 0.015 (±0.028) and 0.015 (±0.019). It significantly increased in Q and QK groups (0.668 (±0.676) and 0.743 (±1.038)). Mean 1-OH-MDZ/MDZ in P, Q were 2.73 (±1.05) and 2.55 (±1.40) while it significantly decreased in K and QK groups (0.11 (±0.05), 0.10 (±0.05)). Moreover, there were no statistically significant differences between QK and K sessions for CYP3A and between QK and Q for CYP2D6 which indicate that there is no interaction between the two metabolic pathways.
CONCLUSION: Simultaneous assessment of CYP3A and CYP2D6 activities can be obtained by low oral doses (micro-cocktail) of MDZ and DEM. Specific inhibitors such as Q or K modulates selectively CYP2D6 or CYP3A activities.
Création de la notice
10/03/2008 10:53
Dernière modification de la notice
20/08/2019 15:23
Données d'usage