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Vol. 31, Issue 5, 606-611, May 2003
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer
Global Research and Development, Groton Laboratories, Groton,
Connecticut
The effects of microsomal concentration on the inhibitory potencies
of four compounds
fluoxetine, quinidine, imipramine, and ezlopitanton heterologously expressed recombinant CYP2D6-catalyzed bufuralol 1'-hydroxylase activity were determined. Increasing microsomal concentration from 0.0088 to 2.0 mg/ml, using additional microsomes not containing cytochrome P450, resulted in a marked increase in IC50 and KI values
for fluoxetine, ezlopitant, and imipramine, when inhibition constants
were calculated using the nominal concentration of inhibitor added to
the incubation mixture. The extent of nonspecific binding of these
inhibitors to microsomes was determined using equilibrium dialysis. The
extent of binding increased with increasing microsomal concentration.
Binding was greatest for ezlopitant, followed by fluoxetine,
imipramine, and quinidine. Correcting inhibition constants for the
extent of nonspecific binding resulted in greater consistency of these
values with differing microsomal protein concentrations. This effect
was also studied with added phospholipid. Inhibition constants
increased with increasing phospholipid, and nonspecific binding
was also observed for these four drugs to phospholipid. This suggests
that the phospholipid component of microsomes possesses some or all of
the responsibility for nonspecific binding, and its effect on
inhibitors of drug-metabolizing enzymes. These findings suggest that
inhibition constants for drugs as inhibitors of microsomal
drug-metabolizing enzymes, such as cytochrome P450, should be corrected
for the extent of nonspecific binding to components of the in vitro
matrix. The implications of this on the prediction of drug-drug
interactions from in vitro data are discussed.
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