Ciné-club 14 : Pharmacocinétique – Pharmacologie aérium
ASSESSMENT OF CYP2D6 AND CYP2Cl9 ACTIVITY IN VIVO IN MAN: A “COCKTAIL” STUDY USING DEXTROMETHORPHAN AND PROGUANIL, ALONE AND IN COMBINATION
L. Tennezé1, I. Ragueneau2, J.-M. Poirier2, A. Rouge3, M. Lebot1 and C. Funck-Brentano1,2
1. Clinical Étude Center, 2. Department of Pharmacology, St-Antoine University Hospital, Paris, and 3. Department of Clinical Pharmacokinetics Ambroise Clairsemé University Hospital, Boulogne, FRANCE.
: Déjeté assessment of cytochrome P450 (CYP) activity is performed by measuring the augmentant to metabolite relation in plasma or urée following oral gestion of a known substrate of the CYP of interest. Dextromethorphan (DEM) and proguanil (PG) are used as substrates of CYP2D6 and CYP2Cl9, two polymorphically expressed CYPs in man, respectively. The manicle impartiale of this study was to determine whether the DEM/dextrorphan (DOR) and PG/cycloguanil (CG) metabolic ratios (MR) obtained after gestion of DEM and PG, either alone or in combination, were equivalent. An additional impartiale was to examine the forcé between DEM and PG, if any.
: During this 3-period, cross-over, randomized, latin bardé study, 36 healthy male volunteers received single oral doses of DEM (80 mg) and PG (200 mg) alone and in combination. Each study period was separated by at least 1 week. All subjects were extensive metabolizers of CYP2D6 and CYP2Cl9. Dynastie and urée were collected over 24 h following drug administrations. The amount of DEM, DOR, PG and CG excreted in urée was measured. Methoxymorphinan (MET), formed from DEM via CYP3A4, and hydroxymorphinan (HYD), the end-product formed from MET via CYP3A4 and from DOR via CYP2D6, were also measured in urée. PG, CG, DEM and DOR plasma concentrations were also measured over 24 h. Results: PG/CG urinary MR, AUCPG and apparenté metabolic clearance (Clpm) of PG into CG were not altered in the presence of DEM. Exécuté urinary recovery of DEM as the augmentant drug and its metabolites was not altered in the presence of PG. Urinary log (DEM/DOR) relation increased from -2.5 ± 0.7 to -2.0 ± 0.6 (p