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The Inhibitory Constant (Ki) and its Use in Understanding Drug Interactions

Summary:

  • The inhibitory constant (Ki) and the 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 for a drug. Since the Ki takes into account the IC50 is its calculation, the Ki is being reported more often by drug companies. 
  • For noncompetitive inhibition of enzymes, the Ki of a drug is essentially the same numerical value as the IC50, whereas for competitive and uncompetitive inhibition the Ki is about one-half that of the IC50's numerical value. 
  • The smaller the Ki, the greater the binding affinity and the smaller amount of medication needed in order to inhibit the activity of that enzyme.  If a Ki is much larger than the maximal drug concentrations that a patient is typically exposed to from typical dosing, then that drug is not likely to inhibit the activity of that enzyme.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed:
October 2015

Explanation

  • If 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 CYP3A4.

    It 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 Ki.4,10 

    Therefore, 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 evaluation. 

    References:

    1. 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.
    2. Atazanavir (Reyataz®) product package insert.  Bristol-Myers Squibb.  Princeton, NJ.  April 2009.
    3. Bachmann KA, Lewis JD.  Predicting inhibitory drug-drug interactions and evaluating drug interaction reports using inhibition constants.  Ann Pharmacother  2005;39:1064-72.
    4. Li 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.
    5. Dexlansoprazole (Kapidex®) product package insert.  Takeda Pharmaceuticals America, Inc.  Deerfield, IL  January 2009.
    6. Esomeprazole (Nexium®) product package insert.  AstraZeneca Pharmaceuticals LP.  Wilmington, DE.  June 2009.
    7. Lansoprazole (Prevacid®) product package insert.  Takeda Pharmaceuticals America, Inc.  Deerfield, IL  January 2009.
    8. Pantoprazole (Protonix®) product package insert.  Wyeth Pharmaceuticals Inc. Philadelphia, PA.  May 2008.
    9. Rabeprazole (Aciphex®) product package insert.  Eisai Co., Ltd.  Tokyo, Japan.  January 2009.
    10. Rodrigues AD, Lin JH.  Screening of drug candidates for their drug-drug interaction potential.  Curr Opin Chem Biol  2001;5:396-401.

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MESH Terms & Keywords

  • Inhibitory Constant, Ki, Drug Interactions