pk ddi

• Drug-Drug Interactions


  The pharmacologic or clinical response to the administration of a drug combination different from that anticipated from the known effects of the two drugs when given alone
• CYP Inhibition


  Decrease in the rate of metabolism of a drug, by another drug (Rapid onset, ↑ plasma [drug], ↑ toxicity)
• CYP Induction


  Induce the enzyme that is responsible for the metabolism of another drug (or even itself) (Slow onset (3 wks),↑ CL, ↓ plasma [drug])
• Levels in the Drug Disposition Pathways where DDIs can occur

  • Absorption
  • GI Metabolism/transport
  • Hepatic metabolism/transport
  • Renal elimination
• Absorption DDIs


  • Antacids raising stomach pH
  • Chelation of drugs in GI tract
  • Altered gastric motility
• Absorption DDI Examples


  • Ketoconazole, itraconazole, ciprofloxacin reduced absorption due to antacids
  • Trovafloxacin reduced absorption due to Maalox antacid
  • Methadone decreasing bioavailability of stavudine
• OATP Transporters


  Intestinal uptake transporters that promote absorption, inhibition leads to decreased absorption and bioavailability
• 1. gp Transporters


  Intestinal efflux transporters, inhibition leads to increased absorption
• Two major types of DDIs

  • Activation (enhanced activity)
  • Inhibition (reduced activity)
• Two mechanisms involved in DDIs

  • Reversible, concentration dependent, rapid effect
  • Slow, involves change in gene expression and altered protein turnover
• Key principles to understand DDIs

  • Which enzymes and transporters are subject to inhibition and induction
  • Which pathways are the drug cleared by
  • What is the therapeutic range of drug
  • What is the potency of inhibiting/inducing drug
  • What is the PK profile of inhibiting/inducing drug
• Drugs with narrow therapeutic range

  • Anticoagulants
  • Antiarrhythmics
  • Anticonvulsants
  • Oral contraceptives
  • Statins
  • HIV Drugs
  • Immunosuppressants
• Clinically important inhibitors


  • Azole antifungals
  • Macrolide antibiotics
  • Protease inhibitors
• Clinically important inducers


  • Rifampicin
  • Carbamazepine
  • Phenytoin
  • Phenobarbital
  • Alcohol
• Clinical consequence of induction

  ↑ Drug metabolism rate, ↓ drug plasma conc., ↓ drug effect, INCREASE DOSE
• Clinical consequence of inhibition

  ↓ Drug metabolism rate, ↑ drug plasma conc., ↑ drug effect, DECREASE DOSE
• When to consider DDIs

  • Initiating new drug therapy
  • Switching drug/drug classes
  • Giving drugs with known interaction potential
  • Withdrawing drugs with known interaction potential
  • Patients with multiple providers in the healthcare system
• Actions to take when faced with a patient on multiple drug therapies

  • Consult a formulary (up to date BNF)
  • Consult a clinical pharmacologist
  • Aim to use drugs with the lowest potential for interaction
  • Stay up to date with new data in the literature
  • Consult a drug interaction web resource
• Clinically important drug interactions occur when a drug potentially inhibits another drug metabolising enzyme (e.g. CYP)
• CYP Inhibition is the most clinically relevant DDI because it occurs almost immediately (compared to CYP induction (days))
• Mechanisms of CYP Inhibition

  • Competitive Inhibition
  • Non-competitive Binding
  • Irreversible Inhibition
• The most common DDI encountered is Inhibition
• Modifiers of DDIs include other drugs, dietary factors (e.g. GFJ), and environmental chemicals
• Drugs


  • italopram
  • chloramphenicol
  • clomipramine
  • cyclophosphamide
  • hexobarbital
  • imipramine N-DeME
  • indomethacin
  • R-mephobarbital
  • moclobemide
  • nelfinavir
  • nilutamide
  • primidone
  • progesterone
  • proguanil
  • propranolol
  • teniposide
  • R-warfarin
• Beta Blockers


  • carvedilol
  • S-metoprolol
  • propafenone
  • Timolol
• Antidepressants


  • amitriptyline
  • clomipramine
  • desipramine
  • imipramine
  • Paroxetine
• Antipsychotics


  • haloperidol
  • perphenazine
  • risperidone
  • 9OH
  • thioridazine
  • Zuclopenthixol
• Other drugs


  • alprenolol
  • amphetamine
  • aripiprazole
  • atomoxetine
  • bufuralol1
  • chlorpheniramine
  • chlorpromazine
  • codeine (O-desMe)
  • debrisoquine
  • dexfenfluramine
  • dextromethorphan
  • duloxetine
  • encainide
  • flecainide
  • fluoxetine
  • fluvoxamine
  • lidocaine
  • metoclopramide
  • methoxyamphetamine
  • mexilletine
  • minaprine
  • nebivolol
  • nortriptyline
  • ondansetron
  • oxycodone
  • perhexiline
  • phenacetin
  • phenformin
  • promethazine
  • propranolol
  • sparteine
  • tamoxifen
  • tramadol
  • venlafaxine
• Anesthetics


  • enflurane
  • halothane
  • isoflurane
  • methoxyflurane
  • Sevoflurane
• Other compounds


  • acetaminophen
  • NAPQI
  • aniline2
  • benzene
  • chlorzoxazone
  • ethanol
  • N,N-dimethylFormamide
  • theophylline
  • 8-OH
• Macrolide antibiotics


  • clarithromycin
  • erythromycin (not 3A5)
  • NOT azithromycin
  • telithromycin
• Anti-arrhythmics


  • quinidine
  • 3OH (not 3A5)
• Benzodiazepines


  • alprazolam
  • diazepam
  • 3OH
  • midazolam
  • triazolam
• Immune Modulators


  • cyclosporine
  • tacrolimus (FK506)
• HIV Antivirals


  • indinavir
  • nelfinavir
  • ritonavir
  • saquinavir
• Prokinetic


  • cisapride
• Antihistamines


  • astemizole
  • chlorpheniramine
  • terfenadine
• Calcium Channel Blockers


  • amlodipine
  • diltiazem
  • felodipine
  • lercanidipine
  • nifedipine2
  • nisoldipine
  • nitrendipine
  • verapamil
• HMG CoA Reductase Inhibitors


  • atorvastatin
  • cerivastatin
  • lovastatin
  • NOT pravastatin
  • simvastatin
• Steroid 6beta-OH


  • estradiol
  • hydrocortisone
  • progesterone
  • testosterone