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Vol. 282, Issue 1, 294-300, 1997
Storr Liver Unit (D.S., A.M.B., L.N., M.M.),
Department of
Medicine, University of Sydney, Westmead Hospital, Westmead, NSW 2145, and Department of Pharmacology (D.S.), University of Sydney, NSW 2006, Australia
The antihypertensive agent diltiazem (DTZ) impairs hepatic drug
metabolism by inhibition of cytochrome P450 (CYP). The accumulation of
DTZ metabolites in serum occurs during prolonged therapy and leads to
decreased DTZ elimination. Thus, DTZ metabolites may contribute to CYP
inhibition. This study assessed the role of human CYPs in microsomal
DTZ oxidation and the capacity of DTZ metabolites to inhibit specific
CYP activities. DTZ N-demethylation varied 10-fold in microsomal
fractions from 17 livers (0.33-3.31 nmol/mg of protein/min). DTZ
oxidation was correlated with testosterone 6
-hydroxylation (r = 0.82) and, to a lesser extent, tolbutamide hydroxylation (r = 0.59) but not with activities mediated by CYP1A2 or CYP2E1. CYP3A4 in
lymphoblastoid cell microsomes catalyzed DTZ N-demethylation but CYP2C8
and CYP2C9 were also active (~20% and 10% of the activity supported
by CYP3A4); seven other CYPs produced little or no N-desmethyl DTZ from
DTZ. The CYP3A4 inhibitors ketoconazole and troleandomycin decreased
microsomal DTZ oxidation, but inhibitors or substrates of CYP2C, CYP2D
and CYP2E1 produced no inhibition. Some inhibition was produced by
-naphthoflavone, a chemical that inhibits CYP1As and also interacts
with CYP3A4. In further experiments, the capacities of DTZ and three
metabolites to modulate human CYP 1A2, 2E1, 2C9 and 3A4 activities were
evaluated in vitro. DTZ and its N-desmethyl and
N,N-didesmethyl metabolites selectively inhibited CYP3A4 activity,
whereas O-desmethyl DTZ was not inhibitory. The IC50 value
of DTZ against CYP3A4-mediated testosterone 6-hydroxylation
(substrate concentration, 50 µM) was 120 µM. The N-desmethyl
(IC50 = 11 µM) and N,N-didesmethyl (IC50 = 0.6 µM) metabolites were 11 and 200 times, respectively, more potent.
From kinetic studies, N-desmethyl DTZ and N,N-didesmethyl DTZ were
potent competitive inhibitors of CYP3A4 (Ki = ~2 and 0.1 µM, respectively). CYP3A4 inhibition was enhanced when
DTZ and N-desmethyl DTZ underwent biotransformation in
NADPH-supplemented hepatic microsomes in vitro, supporting
the contention that inhibitory metabolites may be generated in
situ. These findings suggest that N-demethylated metabolites of
DTZ may contribute to CYP3A4 inhibition in vivo, especially
under conditions in which N-desmethyl DTZ accumulates, such as during
prolonged DTZ therapy.
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