clinicians have not already started to encounter Ki's in the literature and
product package inserts for medications, they will likely encounter them in the
future.1-3 The Ki, in part, becomes important for helping to predict
clinically relevant drug interactions.1,3 Simply
stated, the inhibitory constant (Ki) and the half maximal inhibitory concentration (IC50) of a drug that is known to cause
inhibition of a cytochrome P450 (CYP) enzyme have to do with the
concentration needed to reduce the activity of that enzyme by half.
More specifically the Ki is reflective of the binding affinity and the
IC50 is more reflective of the functional strength of the inhibitor, but both factor in the concentration of drug present to inhibit the enzyme activity. Of note, for drugs that are noncompetitive inhibitors of CYP enzymes, the Ki of a drug is
essentially the same numerical value as the IC50's numerical value, whereas for competitive and
uncompetitive inhibition the Ki is about one-half that of the IC50.3 Therefore, the smaller the Ki, the smaller amount of medication
needed in order to inhibit the activity of that enzyme.
If a Ki is much
larger than the maximal plasma drug concentrations a patient is exposed to from
typical dosing, then that drug is not likely to inhibit the activity of that
enzyme. This effect can also be reflected in the [I]/Ki ratio.1 A
clinically relevant example of this can be seen by evaluating the Ki for proton
pump inhibitors (PPIs) on cytochrome P-450 (CYP) 3A4 enzyme.4 In this
example, the Ki's are significantly higher for most PPIs (42 to 51 mM) than
their respective maximum concentrations (1 to 5.2 mM) in patients who are
either extensive metabolizers or poor metabolizers of 2C219.4-9 Because
the Ki's for PPIs is so much greater than the maximal drug concentrations seen
with typical dosing, most PPIs are not likely to inhibit the activity of
is also important to recognize when interpreting or when reviewing the Ki for a
particular medication that a few factors are known to influence the value
obtained from a study. Those factors include specificity of the
substrate, the binding components in the incubation system and any substrate or
inhibitor depletion.1 As it relates to the incubation system, depending
on the biologic system used, the Ki can fluctuate resulting in a range for the
the use of the Ki is helpful in designating the likelihood that a particular
medication is going to inhibit a particular enzyme and result in a clinically
relevant drug interaction with a substrate for the enzyme. In many cases,
the evaluation of the Ki in relation to the concentration of the inhibitor
present in the body has already been done and is used as the basis for programs
or certain drug information sources to report a particular medication as an
inhibitor or not. It is equally important for clinicians to also
recognize that all medications may or may not have been fully evaluated
depending upon their arrival into the market. In such cases or situations, when
trying to discern the likelihood of a drug interaction occurring between
coadministered medications, clinicians may need to resort to this method of
- United States Food and Drug Administration. Guidance for Industry.
Drug Interaction Studies - Study Design, Data Analysis, and Implications
for Dosing and Labeling. September 2006. Clinical Pharmacology.
- Atazanavir (Reyataz®) product package insert. Bristol-Myers Squibb. Princeton, NJ. April 2009.
KA, Lewis JD. Predicting inhibitory drug-drug interactions and
evaluating drug interaction reports using inhibition constants. Ann
XQ, Andersson TB, Ahlstrom M et al. Comparison of inhibitory effects
of the proton pump inhibiting drugs omeprazole, esomeprazole,
lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450
activities. Drug Metab Dispos 2004;32:821-7.
- Dexlansoprazole (Kapidex®) product package insert. Takeda Pharmaceuticals America, Inc. Deerfield, IL January 2009.
- Esomeprazole (Nexium®) product package insert. AstraZeneca Pharmaceuticals LP. Wilmington, DE. June 2009.
- Lansoprazole (Prevacid®) product package insert. Takeda Pharmaceuticals America, Inc. Deerfield, IL January 2009.
- Pantoprazole (Protonix®) product package insert. Wyeth Pharmaceuticals Inc. Philadelphia, PA. May 2008.
- Rabeprazole (Aciphex®) product package insert. Eisai Co., Ltd. Tokyo, Japan. January 2009.
AD, Lin JH. Screening of drug candidates for their drug-drug
interaction potential. Curr Opin Chem Biol 2001;5:396-401.