Rs. Obach et al., CYTOCHROME P4502D6 CATALYZES THE O-DEMETHYLATION OF THE PSYCHOACTIVE ALKALOID IBOGAINE TO 12-HYDROXYIBOGAMINE, Drug metabolism and disposition, 26(8), 1998, pp. 764-768
Ibogaine is a psychoactive alkaloid that possesses potential as an age
nt to treat opiate and cocaine addiction. The primary metabolite arise
s via O-demethylation at the 12-position to yield 12-hydroxyibogamine.
In this report, evidence is presented that the O-demethylation of ibo
gaine observed in human hepatic microsomes is catalyzed primarily by t
he polymorphically expressed cytochrome P-4502D6 (CYP2D6). An enzyme k
inetic examination of ibogaine O-demethylase activity in pooled human
liver microsomes suggested that two (or more) enzymes are involved in
this reaction: one with a low K-Mapp (1.1 mu M) and the other with a h
igh K-Mapp (>200 mu M). The low K-Mapp activity comprised >95% of tota
l intrinsic clearance. Human liver microsomes from three individual do
nors demonstrated similar enzyme kinetic parameters (mean K-Mapp = 0.5
5 +/- 0.09 mu M and 310 +/- 10 mu M for low and high K-M activities, r
espectively). However, a fourth human microsome sample that appeared t
o be a phenotypic CYP2D6 poor metabolizer possessed only the high K-Ma
pp activity. In hepatic microsomes from a panel of human donors, the l
ow K-Mapp ibogaine O-demethylase activity correlated with CYP2D6-catal
yzed bufuralol 1'-hydroxylase activity but not with other P450 isoform
-specific activities. Quinidine, a CYP2D6-specific inhibitor, inhibite
d ibogaine O-demethylase (IC50 = 0.2 mu M), whereas other P450 isoform
-specific inhibitors did not inhibit this activity. Also, of a battery
of recombinant heterologously expressed human P450 isoforms, only rCY
P2D6 possessed significant ibogaine O-demethylase activity. Thus, it i
s concluded that ibogaine O-demethylase is catalyzed by CYP2D6 and tha
t this isoform is the predominant enzyme of ibogaine O-demethylation i
n humans. The potential pharmacological implications of these findings
are discussed.