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Vol. 29, Issue 12, 1644-1651, December 2001
School of Pharmacy and Pharmaceutical Sciences, University of
Manchester, Manchester, United Kingdom (K.E.K., J.A., J.B.H.); and
Department of Mechanism and Extrapolation Technologies,
GlaxoSmithKline, The Frythe, Welwyn, Herts, United Kingdom (S.E.C.)
Some substrates of cytochrome P450 (CYP) 3A4, the most abundant CYP
in the human liver responsible for the metabolism of many structurally
diverse therapeutic agents, do not obey classical Michaelis-Menten
kinetics and demonstrate homotropic and/or heterotropic cooperativity.
The unusual kinetics and differential effects observed between
substrates of this enzyme confound the prediction of drug clearance and
drug-drug interactions from in vitro data. We have investigated the
hypothesis that CYP3A4 may bind multiple molecules simultaneously using
diazepam (DZ) and testosterone (TS). Both substrates showed sigmoidal
kinetics in B-lymphoblastoid microsomes containing a recombinant human
CYP3A4 and reductase. When analyzed in combination, TS activated the
formation of 3-hydroxydiazepam (3HDZ) and
N-desmethyldiazepam (NDZ) (maximal activation 374 and 205%, respectively). For 3HDZ, Vmax values
remained constant with increasing TS, whereas the S50 and
Hill values decreased, tending to make the data less sigmoidal. Similar
trends were observed for the NDZ pathway. DZ inhibited the formation
6
-hydroxytestosterone (maximal inhibition, 45% of control),
causing a decrease in Vmax but no
significant change to the S50 and Hill values, suggesting that DZ may inhibit via a separate effector site. Multisite rate equation models have been derived to explore the analysis of such complex kinetic data and to allow accurate determination of the kinetic
parameters for activation and inhibition. The data and models presented
are consistent with proposals that CYP3A4 can bind and metabolize
multiple substrate molecules simultaneously; they also provide a
generic solution for the interpretation of the complex kinetic data
derived from CYP3A4 substrates.
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