Food-Drug and DDI

Introduction to Food-Drug and Drug-Drug Interactions

  • Objectives:

    • Understand the processes influencing drug-drug and food-drug interactions.

    • Identify the role of cytochrome P450 enzymes and transporters in drug interactions.

    • Describe considerations for clinically relevant drug interactions.

    • Identify and describe the metabolism-based drug interactions of GI drugs.

Page 3: Abbreviations

  • Abbreviations:

    • AhR: Aryl hydrocarbon receptor

    • AUC: Area under the curve

    • CAR: Constitutive androstane receptor

    • Cmax: Maximum plasma drug concentration

    • CYP: Cytochrome P450

    • GSH: Glutathione

    • GST: Glutathione S-transferase

    • MEC: Minimum effective concentration

    • MTC: Maximum tolerated concentration

    • NAT: N-acetyltransferase

    • PXR: Pregnane X receptor

    • SULT: Sulfotransferase

    • t1/2: Elimination half-life

    • UGT: Uridine diphosphate glucuronosyltransferase

Page 4: Drug Interactions Overview

Types of Interactions

  1. Pharmacokinetic:

    • Absorption, distribution, metabolism, elimination (ADME).

    • Example: Changes in drug bioavailability due to metabolism.

  2. Pharmacodynamic:

    • Additive or opposing effects at the drug action site.

    • Drug synergism and antagonism

    • Factors Influencing Interactions:

    • Transporters

    • Change in pH

Enzyme Induction

  • Inducing agents increase CYP enzyme expression, reducing active drug concentration.

  • Examples of CYP inducers:

    • CYP3A4: Rifampin, St. John’s wort.

    • CYP1A2: Smoking, cruciferous vegetables.

    • Consequence: Decreased drug efficacy (e.g., Tacrolimus with St. John’s wort).

Page 5: Absorption and Metabolism

  • Primary Goals in Drug Interactions:

    • Dose administered, absorption: first-pass metabolism

    • Distribution in tissues and pharmacokinetics in systemic circulation

    • Elimination and pharmacodynamics at the site of action

    • Clinical response and potential toxic effects

Page 6: Pharmacokinetics Parameters

  • Pharmacokinetic Parameters:

    • Cmax: Maximum concentration

    • Tmax: Time to reach Cmax

    • AUC: Area under the curve

      • Higher AUC - more exposure to drug

    • MEC: Minimum effective concentration

    • MTC: Minimum toxic concentration

  • Effects of Metabolism:

    • Can affect all pharmacokinetic parameters including AUC, Cmax, and half-life.

Page 7: Sites of Drug Metabolism

  • Major Metabolic Sites:

    • Liver and Intestine: Main sites with organized enzyme systems

    • Other Organs: Lungs, kidney, skin, brain

  • First-pass Metabolism:

    • Metabolism in gut and liver

    • reduces bioavailability of the parent drug.

Page 8: Drug Metabolism Phases

  • Phase I & II Enzymes:

    • Phase I: Modifies drugs (e.g., CYPs)

    • Phase II: Conjugation reactions (e.g., UGTs)

    • Together these phases contribute to drug metabolism in clinical use.

      Drug Metabolism Basics

      1. Sites of Drug Metabolism:

        • Major: Liver and Intestine (first-pass metabolism reduces bioavailability).

        • Other organs: Lungs, kidneys, skin, brain.

      2. Metabolic Phases:

        • Phase I: Oxidation, reduction, hydrolysis (CYP enzymes).

        • Phase II: Conjugation (UGTs, SULTs).

      3. Outcomes:

        • Detoxification (inactive metabolites).

        • Bioactivation (e.g., prodrugs to active drugs).

        • Production of reactive/toxic metabolites.

Page 9: Pharmacological Outcomes of Drug Metabolism

  • Metabolites Formed:

    • Active Drug: Potentially toxic at high concentrations

      • Inactive Metabolite:

        • Hydrophilic and excreted

    • Active Metabolite:

      • Therapeutic benefits

    • Reactive Metabolite:

      • Can be toxic

  • Examples of Active and Prodrugs:

    • Tamoxifen converts to Endoxifen

    • Diazepam to Oxazepam

    • Imipramine to Desipramine

    • Amitriptyline to Nortriptyline

Page 10: Induction of Drug Metabolism

  • Enzyme Induction:

    • Involves increased expression of drug metabolizing enzymes, leading to increased metabolism and reduced parent drug concentration.

    • Influenced by drugs, health products, dietary components, and substances in the environment.

Page 11: Effects of CYP Induction on Bioavailability

  • Example:

    • St. John's Wort decreases bioavailability of R and S-verapamil by inducing CYP3A4 mediated first-pass metabolism

Page 12: Representative List of CYP Inducers

  • Enzymes and Inducers:

    • CYP1A2: Inducers include smoking, omeprazole

    • CYP2B6: Inducers include efavirenz, rifampin

    • CYP2C19: Rifampin

    • CYP2C9: Inducers include barbiturates and carbamazepine

    • CYP3A4: Inducers include glucocorticoids, St. John's wort

    • Other notable inducers discussed.

Enzyme Inhibition

  • Inhibitors block CYP activity, increasing drug concentrations.

  • Examples:

    • CYP3A4: Grapefruit juice, ketoconazole.

    • CYP2C19: Omeprazole, fluvoxamine.

    • Consequence: Increased toxicity (e.g., atorvastatin + grapefruit juice → risk of rhabdomyolysis).

Page 13: AhR-Mediated CYP1A2 Induction

  • Mechanism:

    • Involves Aryl Hydrocarbon Receptor (AhR) binding and activation leading to increased expression of CYP1A2 enzyme.

Page 14: Consequences of Induction

  • Outcome of Enzyme Induction:

    • Potential incr. metabolism of victim drug leading to either decreased efficacy or increased adverse effects.

    • Acceleration can lead to faster onset or potential toxic side effects.

Page 15: Inhibition of Drug Metabolism

  • Mechanisms of Inhibition:

    • Competitive: Reversed by changes in substrate or inhibitor concentration.

    • Irreversible: Permanent inactivation of CYP enzymes.

Page 16: Effect of Grapefruit Juice on Felodipine

  • Food-Drug Interactions

    1. Grapefruit Juice:

      • Inhibits CYP3A4 → Increases plasma concentration of drugs like felodipine.

      • Consequences: Increased risk of adverse effects (e.g., hypotension, toxicity).

    2. High-Fat Meals:

      • Can delay gastric emptying and slow absorption.

      • May increase absorption of lipophilic drugs.

    3. Calcium-Rich Foods:

      • Bind with tetracyclines and fluoroquinolones, reducing bioavailability.

Page 17: Representative List of CYP Inhibitors

  • Inhibitors and Corresponding Drugs:

    • CYP1A2 inhibitors include cimetidine, ciprofloxacin

    • CYP2D6 inhibitors include fluoxetine, quinidine

    • Grapefruit juice and several other inhibitors affecting CYP3A4 listed.

Page 18: Consequences of Inhibition

  • Outcome of Inhibition:

    • Can lead to increased efficacy or adverse effects, decreased efficacy, slower onset, and toxicity in active drugs due to reduced metabolism.

Page 19: Important Considerations for Clinically Relevant Drug Interactions

  • Key Questions:

    • Outcome of drug metabolism: activation or inactivation?

    • Therapeutic window consideration, metabolic pathways, and specificity of induction/inhibition among others.

Page 20: Summary of Drug Interactions

  • Key Takeaways:

    • Induction results in decreased efficacy due to high metabolism; may require dosage adjustments.

    • Inhibition results in increased AUC of active drugs leading to potential effects or toxicities.


      Active drug (with/without metabolite), Prodrug, Active drug with toxic metabolite•

    • Increase in metabolism as a result of stimulation of protein synthesis(induction )–

    • ↓ AUC/Cmax of the active drug → Decrease in efficacy or treatment failure

    • Drug regimens with inducing agents may require a higher dose of the affecteddrug•

    • Decrease in metabolism as a result of inhibition drug metabolizing enzymeactivity (inhibition)

    • ↑ AUC/Cmax of the active drug à Impaired elimination of the affected drug

    • Prolongation/potentiation of pharmacologic or toxic effects from the affected drug

    • Co-administration of CYP inhibitor leads to lower dose of the affected drug or contraindication of the combination

Page 21: Acetaminophen and Ethanol Interaction

  • Mechanism of Interaction:

    • Ethanol enhances CYP2E1 leading to increased hepatotoxicity due to acetaminophen, highlighting the balance between formation and detoxification.

    • Imbalance between formation and detox of reactive metabolites

    • Toxicity at higher dose of acetaminophen orCYP induction

Page 22: Cases of Drug Interactions

  • Examples:

    • Carbamazepine as CYP3A4 inducer decreasing tacrolimus effectiveness.

    • Ritonavir as an inhibitor increases fluticasone effects significantly.

Page 23: Transporters in Drug Disposition

  • Overview of Transporters:

    • Transporters manage drug concentrations in tissues and elimination rates affecting clearance.

    • Superfamilies include

    • ATP-Binding Cassette ABC (efflux)

    • SLC (uptake) transporters.

      • Solute Carrier (SLC) [e.g. OATP1B1, OCT1]: Primarily uptake transporters

Page 24: Major Drug Transporter Proteins

  • Examples:

    • P-gp (ABCB1) mediating efflux of specific substrates with noted inhibitors and inducers listed.

      Key Enzymes and Transporters

      1. CYP Enzymes:

        • CYP3A4: Metabolizes most drugs (inducers: Rifampin; inhibitors: Ketoconazole, grapefruit juice).

        • CYP2C19: Converts clopidogrel (prodrug) to its active form. Inhibited by omeprazole → reduced anticoagulant effect.

      2. Transporters:

        • P-gp (ABCB1): Efflux transporter.

          • Substrates: Digoxin, paclitaxel.

          • Inhibitors: Ritonavir, cyclosporine.

          • Inducers: Rifampin, St. John’s wort.

Page 25: GI Drug Interactions

  • Examples of GI Drug Interactions:

  • Cimetidine inhibits CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4

    • 5-HT3 receptor antagonists' potential DDI with CYP3A4 inhibitors.

    • Impact of cimetidine on various CYPs and significance in drug interactions.

    • Cyclosporine (CsA), a CYP3A4 substrate - CYP3A4 inhibitors → ↓ metabolism → ↑ CsA plasma concentration– CYP3A4 inducers → ↑ metabolism → ↓ CsA plasma concentration

Page 26: NK1 Receptor Antagonists DDIs

  • Mechanism:

    • CYP3A4 inhibitors/inducers impact plasma levels of NK1 antagonists, affecting therapeutic treatments.

    • CYP3A4 inhibitors/inducers can alter NK1 antagonist plasma profile

Page 27: PPI Drug Interactions

  • Interactions Overview:

  • Extensively metabolized by hepatic CYP2C19 and CYP3A4

  • – Potential DDIs with inhibitors and inducers of CYP2C19 and CYP3A4– CYP2C19 poor metabolizer (slow metabolism) variants → Increased

  • Omeprazole/ Esomeprazole are CYP2C19 inhibitors–

  • Inhibit CYP2C19-mediated conversion of clopidogrel (prodrug) to its active anticoagulant form → Less anticoagulant (therapeutic)effectiveness

    • PPIs like omeprazole can inhibit crucial pathways leading to changes in drug effectiveness, especially clopidogrel.

Examples of Clinically Relevant Interactions

  1. Omeprazole and Clopidogrel:

    • Omeprazole inhibits CYP2C19 → Less activation of clopidogrel → Reduced anticoagulant effect.

  2. Tacrolimus and St. John’s Wort:

    • St. John’s Wort induces CYP3A4 → Decreased tacrolimus levels → Risk of transplant rejection.

  3. Atorvastatin and Grapefruit Juice:

    • CYP3A4 inhibition by grapefruit juice → Increased atorvastatin levels → Risk of rhabdomyolysis.

Page 28: Summary of DDI Impact

  • Focus Areas:

    • Inhibition and activation of pharmacokinetic parameters.

  • Summary

    • Enzyme induction → Faster metabolism, reduced drug levels, possible treatment failure.

    • Enzyme inhibition → Slower metabolism, increased drug levels, potential toxicity.

    • Always assess CYP enzyme interactions and consider patient-specific factors (e.g., diet, genetic polymorphisms).

Key Considerations for DDIs

  1. Therapeutic window of the affected drug (narrow vs. broad).

  2. Metabolism by single vs. multiple enzymes.

  3. Potency of inducers/inhibitors.

  4. Duration of enzyme modulation (reversible or irreversible?).