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Vol. 290, Issue 3, 1116-1125, September 1999
Indiana University School of Medicine, Department of Medicine,
Division of Clinical Pharmacology, Wishard Memorial Hospital,
Indianapolis, Indiana
Diltiazem (DTZ) N-demethylation occurs by cytochrome
P-450 (CYP) 3A based on the following observations: 1) a single enzyme Michaelis-Menten model of metabolite formation, 2) high correlations of
DTZ N-demethylation activity to other CYP3A activities,
3) inhibition of DTZ N-demethylation activity by
triacetyloleandomycin, and 4) DTZ N-demethylation
activity by expressed CYP3A enzymes only. The mean
Kms for DTZ N-demethylation
in human liver microsomes and expressed
CYP3A4(+b5) were 53 and 16 µM,
respectively. A 30-min preincubation of DTZ in expressed CYPs inhibited
CYP3A4(+b5) by 100%, of which 55% was due
to formation of a metabolite intermediate complex (MIC), which is an
inactive form of CYP. MIC was observed in human liver microsomes and
cDNA-expressed CYP3A only. In experiments to assess simultaneous MIC
formation and loss of CYP3A activity, DTZ caused greater than 80%
inhibition of midazolam hydroxylation after a 60-min preincubation in
human liver microsomes. The rate constants for MIC formation and loss
of midazolam hydroxylation activity were equivalent for the line of
best fit for both data sets, which illustrates that MIC formation
causes the inhibition of CYP3A activity. The mechanistic inhibition was
characterized in expressed CYP3A4(+b5),
which exhibited a concentration-dependent formation of MIC by DTZ
(1-100 µM) with an estimated kinact of 0.17 min
1 and KI of 2.2 µM.
The partition ratio for expressed
CYP3A4(+b5) was substrate concentration
dependent and varied from 13 to 86. This study showed that DTZ
inhibition of CYP3A substrate metabolism occurs primarily by MIC formation.
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