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Vol. 281, Issue 3, 1199-1210, 1997
Department of Clinical Pharmacology, Cytochrome P450 (CYP) involved in the two major pathways of imipramine
(IMI) was reappraised using human liver microsomes phenotyped for
S-mephenytoin 4
-hydroxylation in vitro and 11 recombinant human CYP isoforms. Individual Eadie-Hoffstee plots for IMI
N-demethylation and 2-hydroxylation showed a monophasic profile in microsomes obtained from three putative
S-mephenytoin poor metabolizer (PM) livers, whereas the
plots gave a biphasic relationship (except for one case in
2-hydroxylation) in those from the three extensive metabolizer (EM)
livers. Effects of CYP-selective inhibitor/substrate probes on the two
metabolic reactions were examined at the two IMI concentrations (2 and
400 µM) with microsomes obtained from the two PM and three EM livers.
S-mephenytoin inhibited IMI N-demethylation by
50% at the low concentration in microsomes from the EM livers with no
discernible effect on this pathway in those from the PM livers.
Furafylline inhibited the N-demethylation by about 60% at
the low and high substrate concentrations in microsomes from both the
EM and PM livers. Quinidine abolished the 2-hydroxylation at the low
and high concentrations in microsomes from both the EM and the PM
livers. Among the recombinant human CYPs, CYP2C19, 2C18, 2D6, 1A2, 3A4
and 2B6 in rank order catalyzed the N-demethylation, whereas
CYP2D6, 2C19, 1A2, 2C18 and 3A4 catalyzed the 2-hydroxylation. The
Km values obtained from recombinant CYP2C19 and
1A2 approximated those of the high- and low-affinity components from
human liver microsomes for IMI N-demethylation,
respectively. For IMI 2-hydroxylation, the respective
Km values obtained from recombinant CYP2D6 and 2C19 were close to those of the high- and low-affinity components from
human liver microsomes. Our human liver microsomal study using the
near-therapeutic IMI concentration (2 µM) suggests that 1) CYP2C19
and 1A2 are involved in the N-demethylation and the 2-hydroxylation is mediated exclusively by CYP2D6 and partially by
CYP2C19 in the EM livers, and 2) CYP1A2 and 2D6 play a major role in
IMI N-demethylation and 2-hydroxylation, respectively, in
the PM livers. Our recombinant human CYP isoform study, in general,
supports this conclusion.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
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