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Vol. 25, Issue 12, 1347-1353, 1997
-Acetylmethadol (LAAM), norLAAM, and
Methadone
Center for Human Toxicology (D.E.M., M.E.A.), Department of
Pharmacology and Toxicology, College of Pharmacy, University of Utah;
and
Laboratory of Clinical Pharmacology (R.J.P., J.M.C., J.M.S.),
Center for Drug Evaluation, U.S. Food and Drug Administration
The N-demethylation of LAAM, norLAAM, and methadone has
been investigated in human liver microsomes and microsomes containing cDNA-expressed human P450s. Gas chromatography/mass spectrometry methods allowed detection of norLAAM and dinorLAAM formation from LAAM,
dinorLAAM formation from norLAAM, and EDDP and EMDP formation from
methadone. The rates of N-demethylation varied 4- to 7-fold in microsomes from four different donors with activities for LAAM and
norLAAM consistently greater (5- to 14-fold) than for methadone. The
N-demethylation of LAAM, norLAAM, and methadone were
significantly inhibited by ketoconazole. IC50s
could be determined for ketoconazole inhibition of LAAM and norLAAM
N-demethylation of 1.6 and 1.1 µM, respectively. The
ability of ketoconazole to reduce methadone N-demethylation
below 40% varied in regard to liver donor. No other P450-selective
inhibitors reduced the average activities more than 43%.
cDNA-expressed P450 3A4 N-demethylated LAAM, norLAAM, and
methadone at greater rates than the other cDNA-expressed P450s studied
(1A2, 2C9, 2D6, or 2E1). P450 3A N-demethylation of LAAM, norLAAM, and methadone exceeded the next most active P450,
respectively, by at least 2.5, 9.6, and 13.4 times when expressed per
milligram protein and by 18.2, 6.0, and 6.1 times when expressed per
nanomole P450. These results suggest that P450 3A4 is the primary site of N-demethylation of LAAM, norLAAM, and methadone in human
liver. Although other enzymes may also be capable of
N-demethylating these compounds, identification of specific
enzymes, except P450 3A4, has yet to be established. Knowledge of these
enzymatic pathways is essential for assessment of the impact of
metabolic drug-drug interactions on therapeutic success and/or adverse
events.
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