Session 14 : Pharmacocinétique – Pharmacologie clinique

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Session 14 : Pharmacocinétique – Pharmacologie clinique

137

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. Roux3, M. Lebot1 and C. Funck-Brentano1,2

1. Clinical Investigation Center, 2. Department of Pharmacology, St-Antoine University Hospital, Paris, and 3. Department of Clinical Pharmacokinetics Ambroise Paré University Hospital, Boulogne, FRANCE.

Objectives

: Indirect assessment of cytochrome P450 (CYP) activity is performed by measuring the parent to metabolite ratio in plasma or urine following oral administration 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 main objective of this study was to determine whether the DEM/dextrorphan (DOR) and PG/cycloguanil (CG) metabolic ratios (MR) obtained after administration of DEM and PG, either alone or in combination, were equivalent. An additional objective was to examine the interaction between DEM and PG, if any.

Methods

: During this 3-period, cross-over, randomized, latin square 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. Plasma and urine were collected over 24 h following drug administrations. The amount of DEM, DOR, PG and CG excreted in urine 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 urine. PG, CG, DEM and DOR plasma concentrations were also measured over 24 h. Results: PG/CG urinary MR, AUCPG and partial metabolic clearance (Clpm) of PG into CG were not altered in the presence of DEM. Total urinary recovery of DEM as the parent drug and its metabolites was not altered in the presence of PG. Urinary log (DEM/DOR) ratio increased from -2.5 ± 0.7 to -2.0 ± 0.6 (p