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Vol. 29, Issue 1, 70-75, January 2001
Drug Metabolism Research, Pharmacia Corporation, Kalamazoo,
Michigan
In human liver microsomes, triazolam is principally metabolized by
CYP3A4 to form two metabolites, 1'-hydroxytriazolam (1'OHTz) and
4-hydroxytriazolam (4OHTz). The velocity of 1'OHTz formation was found
to decrease at higher triazolam concentrations (>200 µM), indicative
of "substrate inhibition". Coincubation of
[14C]triazolam with authentic metabolite standards of
either 1'OHTz or 4OHTz up to 30 µM did not significantly inhibit the
rate of [14C]1'OHTz formation. The effects of secondary
compounds on triazolam oxidation were shown to be product-specific,
producing either activation or inhibition depending on the triazolam
metabolite monitored. When human liver microsomes were supplemented
with exogenous human cytochrome b5, it was
observed that substrate inhibition was attenuated and the resulting
increase in 1'OHTz formation, relative to control (nonsupplemented)
incubations, corresponded to a decrease in the ratio of 4OHTz to
1'OHTz. In contrast, when cofactor (e.g., 100 µM NADPH) was rate
limiting, the metabolite ratio (4OHTz/1'OHTz) was markedly increased
over the entire substrate concentration range (0.5-1000 µM). To
explain these kinetic observations, a two-site binding model is
proposed in which triazolam is hypothesized to bind within the CYP3A4
active site in spatially distinct orientations, which may lead to the formation of either the 1'-hydroxytriazolam or 4-hydroxytriazolam. Differential inhibition/activation is consistent with this two-site model and substrate inhibition is hypothesized to result from competition between the two sites for reactive oxygen.
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