Phenotypic differences in dextromethorphan metabolism.
Polymorphic differences in dextromethorphan metabolism were observed in three studies conducted in a total of 44 subjects (of Dutch origin) administered 60 mg dextromethorphan hydrobromide as an OROS tablet. Mean plasma dextromethorphan (DM) concentrations after a single dose and at steady state were 4-75 times higher in the poor metabolizers (PM) relative to the extensive metabolizers (EM). Following a single dose, the mean areas under the plasma concentration-time curve (AUC, 0-24 hr) of DM, total dextrorphan (DR), and total 3-hydroxymorphinan (HM) were 6.9-fold higher, 17.4-fold lower, and 11-fold lower, respectively, for the PM than for the EM. Correspondingly, steady-state AUC values were 52.8 times higher, 6.7 times lower, and 3.3 times lower for DM, total DR, and total HM, respectively, for the PM relative to the EM. Drug/metabolite ratios (DMR) for amounts excreted in the urine of DR and HM indicated polymorphism in O-demethylation of DM since DMR for PM was 352 and 338 times higher than that for EM for DR and HM, respectively. However, polymorphism in N-demethylation was not observed. Ratios of conjugated/free dextrorphan and 3-hydroxymorphinan excreted in the urine suggest also a lack of conjugative capacity in the PM, relative to the EM. The overall incidence of PM was 9.1% in this population.
Vetticaden
S J
SJ
International Drug Registration, Rockville, Maryland 20850.
Cabana
B E
BE
Prasad
V K
VK
Purich
E D
ED
Jonkman
J H
JH
de Zeeuw
R
R
Ball
L
L
Leeson
L J
LJ
Braun
R L
RL
D000284:Administration, Oral; D003915:Dextromethorphan / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D003917:Dextrorphan / Q000097:blood; D006801:Humans; D007981:Levorphanol / Q000031:analogs & derivatives*; D010641:Phenotype
D003917:Dextrorphan; D007981:Levorphanol; D003915:Dextromethorphan; C054116:norlevorphanol