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Dear reader,
I am looking for an answer to the following problem.
When preforming inhibition studies in vitro with human liver
microsomes, one can determine a Ki value, that is the concentration
of the inhibitor that reduces the formation speed of the metabolite
(for the pathway of interest) with 50 % at low substrate
concentrations ([S]<dissociation constant, or an affinity constant, of the
inhibitor-enzyme complex. This Ki value, once determined for a
specific inhibitor and a specific iso-enzyme should be constant. In
the literature however the Ki varies with the reaction studied.
Is this Ki value, altough theoretically constant, dependent on the
substrate and the reaction studied ? If so, how can one explain this
phenemenon ? Is there an explanation on moleculair level ?
Sincerely yours,
Alex Hemeryck, Ph.D. student
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Alex Hemeryck
Pharmacist
Heymans Institute of Pharmacology
University of Ghent
Medical School
De Pintelaan 185
B-9000 Gent
Tel: +32-9-2403370
Fax: +32-9-2404988
e-mail: Alex.Hemeryck.-at-.rug.ac.be
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Alex,
Your definition of Ki is really the definition for the IC50 of an inhibitor in
the presence of a specific substrate.Ki can be calculated from the IC50 using
the equation: Ki=IC50*Km/(S+Km), where S is the conc. of substrate, and Km is
the substrate conc. (in the absence of inhibitor) at which the velocity of the
reaction is half-maximal. For derivation and molecular basis, see PRINCIPLES OF
DRUG ACTION,third ed., Pratt and Taylor. The Ki of an inhibitor for inhibition
of a particular substrate (fixed Km) is constant. For a different substrate, Km
is different, and so is the Ki. Hope this helps.
Arnab Mukherjee
Univ. of Tennessee, Memphis
Amukherjee.at.am.utmem.edu
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)