Midterm 1: P450 Drug Metabolism DDIs: Inhibition Flashcards Preview

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Flashcards in Midterm 1: P450 Drug Metabolism DDIs: Inhibition Deck (12):

The magnitude of the inhibition will be dose dependent

  • Higher inhibitor doses provide higher blood levels.
  • Inhibition of object drug metabolic clearance depends on the dose and blood levels of [I].
  • Below: example where the extent of inhibition, is dependent upon the plasma concentration of the inhibitor (fluvoxamine). In this plot the Y-axis shows the extent of inhibition (bigger numbers=more inhibition). 

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Reversible Inhibition: 

  • The inhibitor “competes” for enzyme with the object drug. 
  • Increasing the concentration of inhibitor shifts equilibrium to the left 
  •  Ki; concentration of inhibitor required to bind up half of enzyme. Affinity. Lower Ki, more potent inhibitor. 

  • Each enzyme-inhibitor pair has a characteristic and constant Ki. Can predict the effect that will be observed on all object drugs metabolised by that enzyme.

  • Graphs of in vivo data allow us to “calibrate” in vivo effect of an interactant drug.

  • We can determine a Ki for an inhibitor enzyme pair by doing in vitro experiments in microsomes. If we know the plasma levels of the inhibitor we can predict the magnitude of an interaction from the I/Ki ratio and specific information about the percent contribution of the enzyme to the clearance of the object drug. 

  • Most inhibitory DDI’s are the result of reversible competitive inhibition of a P450 enzyme by an interactant drug. 

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Reversible Inhibition: Equations and Such 

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Irreversible Inhibition (Mechanism based enzyme inactivation (MBI)): 

  • enzyme attempts to metabolize inhibitor and produces a reactive intermediate that binds covalently (active site amino acids or the heme) to produce an irreversible enzyme that is no longer active. 
  • The body must produce new enzyme molecules before drug metabolism activity can be restored. 
  • The inhibition of the enzyme requires time (hours to days) to occur since it depends on a catalytic rate. Mechanism based inhibition is is time dependent. 
  • Many alkylamine containing drugs undergo sequential metabolism to produce reactive intermediates the bind directly to the heme iron of P450. These stable adducts are called metabolite intermediate complexes or MICs. Drugs that do this and cause DDIs include troleandomycin, erythromycin and diltiazem. 

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Effect of an interactant drug will be observed on all object drugs metabolised by that enzyme. 

  • The magnitude of the effect at an equivalent dose of the inhibitor will depend upon how much of the object drug clearance is due to that enzyme. 
  • Here fluvoxamine is an inhibitor of CYP1A2. The data are taken from individual clinical studies. 

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 magnitude of the inhibitory effect depends upon ...(graph)

  • dose of the inhibitor and the fraction of the drug that is metabolised by the enzyme that is inhibited. 
  • Maximum 2 fold effect is observed. About 60% of theophylline clearance is due to CYP1A2 so a maximum effect is observed even as the plasma levels of ciprofloxacin continue to climb. If the clearance of theophylline was totally due to CYP1A2 we would predict a rising straight line from this plot. 

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Mathmatically, what determines the magnitude of the effect observed 

  • Generally I/Ki ratios and the fraction of the object drug clearance that is due to the inhibited enzyme (fm) determines the magnitude of the effect observed. 

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Sulfaphenazole and tolbutamide 

  • Below is shown the effect of sulfaphenazole (interactant drug) on tolbutamide (object drug)
  • Note that the amount of tolbutamide (cleared mostly by CYP2C9) increases substantially when sulfaphenazole is added to the dosing regimen. Note also that the interaction takes time to develop and dissappear. 
    • tolbutamide hals a long half-life because takes time for response to appear
  • Corollary: Any drug that is substantially cleared by CYP2C9 will experience a drug/drug interaction with sulfaphenazole.  

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 cimetidine inhibition

  • Inhibits CYP2C9  
  • half-lives of (S)-warfarin and tolbutamide are both increased by cimetidine. (Prothrombin times greater than 30-are associated with uncontrolled bleeding). 
  • worry about onset AND removal 

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A more complex example of a different kind (the parent drug is toxic and a metabolite is active) 

  • Terfenadine (Seldane) was popular non- sedating H1 antagonist used to treat allergies. 
  • When marketed, nothing was known about what enzymes produced it’s metabolites.
  • blood levels of terfenadine were very low relative to levels of its metabolites. suggested antihistamine effect may be due to a metabolite.
  • CYP3A4 converts almost all of the dose (>99%) to metabolites before the oral drug reachessystemic circulation
    • a massive first pass


  • cardiotoxicity, increase in Q-T interval, when the drug was given with CYP3A4 inhibitors such as ketoconazole, grapefruit juice, erythromycin, itraconazole and others. This effect due to tergenadine induced blockage of the hERG channel, a potassium channel in the heart tissue. hERG blockade can result in ventricular fibrillation and death. 

  • antihistamine effects due mostly to the major circulating metabolite terfenadinic acid, while the cardiotoxic effect was due to the terfenadine itself.

  • Terfenadine was removed from the marketThe acid metabolite (fexofenadine: Allegra) has replaced it

  • Many amine containing drugs are now known to occasionally cause QT prolongation by binding to the hERG channel. Thus inhibition of their metabolism can lead to a hightened risk of this reasonably common off-target toxicity. 

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An example of an intentional DDI  

  • Ritonavir (Norvir) is a first generation HIV-protease inhibitor (PI). Now widely used as a boosting agent in the treatment of HIV. Has potent off-target inhibitory effect on CYP3A4 dependent metabolism of other protease inhibitors such as lopinavir and saquinavir.
    • Ex: AUC to saquinavir is increased 17 fold by co-administration of RTV. Currently two of the four preferred drug regimens remploy RTV as an adjuvant. 
  • Co-formulated dosage form (Kaletra; (lopinavir-ritonavir)) and has been applied to the development of other co- formulations as well as an alternate boosting agent. Kaletra is the only PI-enhanced regimen co-formulated into a single pill. 
  •  RTV causes time dependent loss of enzyme activity in vitro and clinical studies have established that otherwise sub-therapeutic RTV doses of 100 mg/day are sufficient to “knock out” CYP3A4 activity in vivo

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large population of RTV-boosted patients are at a high risk of unintended but profound drug drug interactions with object drugs significantly metabolized by CYP3A4. 

  • Flonase Interaction
    • Cases of significant adrenal suppression secondary to an interaction between ritonavir and inhaled/intranasal fluticasone. 

  • Midazolam Interaction 

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