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Vol. 297, Issue 1, 410-422, April 2001
-Acetylmethadol (LAAM) by
Human Liver Cytochrome P450: Involvement of CYP3A4 Characterized by
Atypical Kinetics with Two Binding Sites
Departments of Anesthesiology and Medicinal Chemistry, University
of Washington, and the Puget Sound Veterans Affairs Medical Center,
Seattle, Washington (E.D.K.); and Department of Anesthesiology, Osaka
City University Medical School, Osaka, Japan (Y.O.)
levo-
-Acetylmethadol (LAAM) is a long-acting opioid
agonist prodrug used for preventing opiate withdrawal. LAAM undergoes bioactivation via sequential N-demethylation to
nor-LAAM and dinor-LAAM, which are more potent and longer-acting than
LAAM. This study examined LAAM and nor-LAAM metabolism using human
liver microsomes, cDNA-expressed CYP, CYP isoform-selective chemical
inhibitors, and monoclonal antibody to determine kinetic parameters for
predicting in vivo drug interactions, involvement of constitutive CYP
isoforms, and mechanistic aspects of sequential
N-demethylation. N-Demethylation of LAAM
and nor-LAAM by human liver microsomes exhibited biphasic Eadie-Hofstee
plots. Using a dual-enzyme Michaelis-Menten model, Km values were 19 and 600 µM for nor-LAAM
and 4 and 450 µM for dinor-LAAM formation, respectively. LAAM and
nor-LAAM metabolism was inhibited by the CYP3A4-selective inhibitors
troleandomycin, erythromycin, ketoconazole, and midazolam. Of the
cDNA-expressed isoforms examined, CYP2B6 and 3A4 had the highest
activity toward LAAM and nor-LAAM at both low (2 µM) and high (250 µM) substrate concentrations. N-Demethylation of LAAM
and nor-LAAM by expressed CYP3A4 was unusual, with hyperbolic velocity
curves and Eadie-Hofstee plots and without evidence of positive
cooperativity. Using a two-site model, Km
values were 6 and 0.2 µM, 1250 and 530 µM, respectively. Monoclonal
antibody against CYP2B6 inhibited CYP2B6-catalyzed but not microsomal
LAAM or nor-LAAM metabolism, whereas troleandomycin inhibited
metabolism in all microsomes studied. The ratio [dinor-LAAM/(nor-LAAM plus dinor-LAAM)] with microsomes and CYP3A4 decreased with increasing LAAM concentration, suggesting most dinor-LAAM is formed from released
nor-LAAM that subsequently reassociates with CYP3A4. Based on these
results, we conclude that LAAM and nor-LAAM are predominantly
metabolized by CYP3A4 in human liver microsomes, and CYP3A4 exhibits
unusual multisite kinetics.
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