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Vol. 29, Issue 11, 1514-1520, November 2001
Department of Basic Pharmaceutical Sciences, School of Pharmacy,
West Virginia University, Morgantown, West Virginia
Dextromethorphan (DXM) is a widely used probe drug for human
CYP2D6 activity both in vitro and in vivo. In humans, DXM is metabolized to dextrorphan (DXO), as well as 3-methoxymorphinan (MEM)
and 3-hydroxymorphinan (HYM). The formation of MEM has been attributed
primarily to CYP3A4, and the use of DXM has been debated as a
simultaneous probe for CYP3A4 and CYP2D6 activities. Recently, we found
that highly purified CYP2D6 has significant DXM
N-demethylase activity in addition to its well known DXM
O-demethylase activity. Therefore, we desired to further
compare the contribution to DXM metabolism by individual human
cDNA-expressed cytochromes P450, including 2C8, 2C9, 2C18, 2C19,
2D6, 2B6, and 3A4. Metabolites were quantified following separation by
high-pressure liquid chromatography and apparent Michaelis-Menten
constants determined for the appearance of DXO and MEM. Intrinsic
clearance values were estimated for each P450 and normalized using the
average percentage content and relative activity factor approaches for
comparison. Simplified kinetic models (when [S] 
Km,
Vmax/Km = Vo/[S]) were used at fixed DXM
concentrations of 20 (for DXM N-demethylation) and 0.2 µM (for DXM O-demethylation), as well as 2 µM to
mimic plasma DXM concentrations in human extensive metabolizers. The
results confirm that CYP2D6 contributes at least 80% to the formation of DXO, and CYP3A4 contributes more than 90% to the formation of MEM.
All of our in vitro results are consistent and indicate that DXM as a
marker for monitoring both CYP2D6 and CYP3A activities is practical in
an average human or human liver microsomal preparation.
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