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Vol. 30, Issue 12, 1497-1503, December 2002
Department of Physical and Metabolic Science, AstraZeneca R&D
Charnwood, Loughborough, United Kingdom
The apparent intrinsic clearance of 13 drugs has been determined
using rat liver microsomes at three different concentrations of
microsomal protein. The kinetics was studied using the in vitro half-life method. The nonspecific binding of these drugs to the microsomes was also studied under the same conditions, except for
cofactor removal, using equilibrium dialysis. The intrinsic clearances
are shown to be dependent on the microsomal concentration, but are
approximately constant when corrected for the extent of nonspecific
binding to the microsomes. The large difference between observed
intrinsic clearance and unbound intrinsic clearance that exists for
some compounds, particularly lipophilic bases, is highlighted. A simple
model has been developed for understanding the binding of compounds to
microsomes and is demonstrated to accurately predict the extent of
microsomal binding at one concentration of microsomes from measurement
at another. The binding of a further 25 drugs to rat liver microsomes
at a microsomal concentration of 1 mg/ml was also studied, along with
measurements of lipophilicity using octanol-water partition
coefficients. It is shown that the extent of microsomal binding is
correlated with lipophilicity, but that basic compounds show a
different behavior to acidic and neutral compounds. Microsomal binding
is shown to be best predicted using a model where logP is used for
basic compounds, and logD7.4 is used for acidic and neutral
compounds. This model has been developed further so that the extent of
binding to microsomes of any given concentration can be estimated
purely from a knowledge of lipophilicity and ionization.
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