Drug Interactions Clinical Pharmacology Spring Course 2006

1
Drug InteractionsClinical PharmacologySpring
Course 2006

• M. E. Blair Holbein, Ph.D.
• Clinical Pharmacologist
• Presbyterian Hospital

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Why study drug interactions?
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Clinical Significance of Drug Interactions

• Over 2 MILLION serious ADRs and 100,000 deaths
  yearly
• ADRs 4th leading cause of death ahead of
  pulmonary disease, diabetes, AIDS, pneumonia,
  accidents and automobile deaths
• Greater than total costs of cardiovascular or
  diabetic care
• ADRs cause 1 out of 5 injuries or deaths per year
  to hospitalized patients
• Mean length of stay, cost and mortality for ADR
  patients are DOUBLE that for control patients
• Account for 6.5 hospital admissions
• Nursing home patients ADR rate50,000 yearly
• Ambulatory patients ADR rateunknown
• Many clinical implications
• Libby Zion case
• Clinical Trials, OPI
• International Intrigue?

Ref Institute of Medicine, National Academy
Press, 2000, Lazarou J et al. JAMA
1998279(15)12001205, Gurwitz JH et al. Am J
Med 2000109(2)8794.Johnson JA et al. Arch
Intern Med 1995155(18)19491956, Leape LL et
al. N Engl J Med 1991324(6)377384, Classen DC
et al. JAMA 1997277(4)301306
4
er
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Preventable drug interactions

• 1/3 of adverse drug events
• and
• 1/2 cost.

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Definition

• A drug interaction is defined as a measurable
  modification (in magnitude or duration) of the
  action of one drug by prior or concomitant
  administration of another substance (including
  prescription and nonprescription drugs, food, or
  alcohol)
• May be harmful toxicity, reduced efficacy
• May be beneficial synergistic combinations,
  pharmacokinetic boosting, increased convenience,
  reduced toxicity, cost reduction .

Wright JM. 2000. Drug Interactions. In
Carruthers SG, Hoffman BB, et al. , ed. Melmon
and Morrellis Clinical Pharmacology Basic
Principles in Therapeutics, 4th ed. New
YorkMcGraw-Hill.
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Characterizing Drug Interactions

• Mechanism
• Pharmacodynamic
• Receptor inhibition
• Additive effects
• Pharmacokinetic
• Altered absorption, distribution, metabolism, or
  elimination

• Interacting agents
• Drug - Disease
• Drug-drug
• Prescription
• Non-prescription
• Illicit, recreational
• Food, supplements, herbal products

• Clinical Significance
• Major
• Substantial morbidity and mortality
• Therapy altering
• Manageable
• Little or no change in therapy
• Optimize therapy
• Intentional
• Additive or synergistic effects
• Enhanced pharmacokinetics

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Mechanisms of Interactions

• Pharmacodynamic
• Receptor
• Non-receptor

• Pharmacokinetic
• Absorption
• Distribution
• Metabolism
• Excretion

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Mechanisms of Interactions

• Pharmacodynamic
• Receptor
• Non-receptor

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Pharmacodynamic Pharmacological

• Interaction at the drug receptor
• Activity is function of intrinsic activity and
  affinity for receptor
• Agonist and antagonists
• Effect also function of concentration at receptor
• Effect can be additive
• Several agents that act via the same receptor
• Example, several agents with anticholinergic
  activity or side effects can result in serious
  anticholinergic toxicity especially in elderly
  patients.

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Pharmacodynamic Physiological

• Agents that can act in concert or in opposition
  via different cellular mechanisms.
• Both theophylline and b-receptor agonists can
  cause bronchiolar muscle relaxation
• Sensitization of myocardium to arrhythmogenic
  action of catecholamines by general anesthetics.
• Combinations of antihypertensive (can be
  intentional)

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Pharmacodynamic Altered physiology

• Altered cellular environment
• Aging effects
• Blunted sympathetic nervous system blunted
  responses
• Agents that change the state of the host
• Ex. Hypokalemia caused by diuretics increases
  toxicity of digoxin.

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Pharmacodynamic Neutralization

• Neutralization systemically in the host (as
  opposed to prior to absorption)
• Protamine used to neutralize heparin
• Purified antidigoxin Fab fragments used to treat
  digoxin toxicity

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Mechanisms of Interactions

• Pharmacodynamic
• Receptor
• Non-receptor

• Pharmacokinetic
• Absorption
• Distribution
• Metabolism
• Excretion

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Mechanisms of Interactions

• Pharmacokinetic
• Absorption
• Distribution
• Metabolism
• Excretion

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Mechanisms of Interactions

• Pharmacokinetic
• Absorption
• Distribution
• Metabolism
• Excretion

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Pharmacokinetic Absorption

• Alters rate that drug enters the system with
  altered level or time to peak
• Mechanisms
• Physical interaction, chelation, binding. e.g.
  tetracyclines and cations
• Altered GI function changes in pH
  (ketoconazole), motility, mucosal function,
  metabolism, absorption sites, perfusion

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Absorption in the gut

• Sucralfate, some milk products, antacids, and
  oral iron preparations
• Omeprazole, lansoprazole,H2-antagonists
• Didanosine (givenas a buffered tablet)
• Cholestyramine

• Block absorption of quinolones, tetracycline, and
  azithromycin
• Reduce absorption of ketoconazole, delavirdine
• Reduces ketoconazole absorption
• Binds raloxifene,thyroid hormone, and digoxin

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Interactions Presystemic Elimination

• Gut transit and metabolism
• Intestinal wall CYP3A4 metabolizes a number of
  drugs
• Inhibition/induction results in altered
  bioavailability
• Ex grapefruit juice inhibits intestinal CYP3A4
• Results in increased bioavailability of calcium
  channel blockers (dihydropyridine), cyclosporin,
  saquinavir (HIV-1 protease inhibitors),
  carbamazepine, lovastatin, terazosin, triazolam
  and midazolam.
• High intrinsic hepatic clearance dependent upon
  hepatic blood flow
• Inhibition results in increased bioavailabilty.
• Propranolol, metoprolol, labetalol, verapamil,
  hydralazine, felodipine, clhlorpromazine,
  imipramine, amitriptyline, morphine

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First-Pass Metabolism after Oral Administration
of a Drug, as Exemplified by Felodipine and Its
Interaction with Grapefruit Juice
Wilkinson, G. R. N Engl J Med 20053522211-2221
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Some Common Drugs with Low Oral Bioavailability
and Susceptibility to First-Pass Drug
Interactions
Wilkinson, G. R. N Engl J Med 20053522211-2221
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Consequences of the Inhibition of First-Pass
Metabolism, as Exemplified by the Interaction
between Felodipine and Grapefruit Juice
Wilkinson, G. R. N Engl J Med 20053522211-2221
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Induction of P-glycoprotein and Intestinal CYP450

• Intestinal epithelium with CYP450
• Sufficient amout to result in presystemic
  clearance of some drugs
• Highly variable
• Enterocytes have transporter proteins
• Organic anion-transporting polypeptide (OATP)
• Organic cation transporters (OCTs)
• P-glycoprotein (P-gp)
• Product of human multidrug resistance gene (mdr1)
• Contributesto resistance to a variety of
  chenotherapeutic agents
• Decreases the intracellular accumulation of
  anticancer drugs
• Efflux transporter in Gi epithelium, liver,
  kidney, edothelial cells of blood-brain barrier
• Complements CYP450 interactions

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Intestinal Transporter - P-glycoprotein
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Intestinal Monoamine Oxidase

• Intestinal MAO inhibited by nonselective
  irreversible agents and inhibit metabolism of
  dietary tyramine resulting in increased release
  of norepi from sympathetic postganglionic neurons
• Less problematic for selective MAO B inhibitor
  selegiline and reversible agent moclobemide

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Mechanisms of Interactions

• Pharmacokinetic
• Absorption
• Distribution
• Metabolism
• Excretion

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Pharmacokinetic Distribution

• Protein-binding displacement
• Relative to
• Concentration - a high concentration of one drug
  relative to another will shift the binding
  equilibrium
• Relative binding affinity - only relatively
  highly bound drugs will be effected
• Volume of distribution - small Vd allows for
  greater proportional effect
• Therapeutic index - mostly drugs with a narrow TI
  are clinically significant
• Alterations in protein-binding capacity
• hypoalbuminemia (acidic drugs)
• a1-acid glycoprotein (basic drugs)
• acute phase reactants

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Pharmacokinetic Distribution

• Protein-binding displacement
• Effect is rapid and transient and usually
  compensated by increased elimination
• May result in transient pharmacologic effect
• Overall result is unpredictable
• New steady-state attained

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Pharmacokinetic Distribution

• Cellular distribution interactions
• Cellular transport systems
• Promiscuous and affect several agents requiring
  active transport
• Best studied example is P-glycoprotein (PGP) an
  organic anion transporter system.
• Cyclosporin A, quinidine, verapamil, itraconazole
  and clarithromycin inhibit PGP
• Some correlation with CYP3A4 affinities
• May be significant for some anticancer drugs

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Mechanisms of Interactions

• Pharmacokinetic
• Absorption
• Distribution
• Metabolism
• Excretion

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Drug Metabolism

• Phase I
• Oxidation
• Cytochrome P450 monooxygenase system
• Flavin-containing monooxygenase system
• Alcohol dehydrogenase and aldehyde dehyddrogenase
• Monoamine oxidase (Co-oxidation by peroxidases)
• Reduction
• NADPH-cytochrome P450 reductase
• Reduced (ferrous) cytochrome P450
• Hydroloysis
• Esterases amd amidases
• Epoxide hydrolase
• Phase II
• Glutathione S-transferases
• UDP-Glucoron(os)yltranasferases
• N-Acetyltransferases
• Amino acid N-acyl transferases
• Sulfotransferases

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Interactions in the Phases of Drug Metabolism

• Drug interactions due to metabolic effects nearly
  always due to interaction at Phase I enzymes,
  rather than Phase II
• CYP450 system responsible for the majority of
  oxidative reactions and subsequent interactions
• Significant polymorphism in many.
• CYP2C9, CYP2C19, and CYP2D6can be even be
  genetically absent!
• Drugs may be metabolized by a single isoenzyme
• Desipramine/CYP2D6 indinavir/CYP3A4
  midazolam/CYP3A caffeine/CYP1A2
  omeprazole/CYP2C19
• Drugs may be metabolized by multiple isoenzymes
• Most drugs metabolized by more than one isozyme
• Imipramine CYP2D6, CYP1A2, CYP3A4, CYP2C19
• If co-administered with CYP450 inhibitor, some
  isozymes may pick up slack for inhibited
  isozyme.
• Drugs may be metabolized by a combination of
  enzymatic systems.

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Pharmacokinetic Elimination - Metabolism

• Interactions can result from increased as well as
  decreased metabolism
• Clinical relevance is dependent upon timing of
  interaction, therapeutic index of affected drug,
  duration of therapy, metabolic fate of affected
  drug, metabolic capacity of host.
• Host factors include age, genetic makeup
  (acetylation, CYP2D6), nutritional state, disease
  state, hormonal milieu, environmental and
  exogenous chemical exposure.
• P450 isoenzymes are variously affected.
• Isoenzymes characterized
• Substrates
• Inhibiting agents
• Inducing agents
• No consistent correlation of substrate versus
  inhibitor or inducer
• Good reference http//medicine.iupui.edu/flockhar
  t/ (alias www.drug-interactions.com)

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Pharmacokinetic Elimination - Metabolism

• Characteristics of interactions with DECREASED
  metabolism
• Inhibition of metabolizing enzymes
• Timeframe is rapid
• Duration and extent of effect is dependent upon
  concentration of agents and enzyme affinities.
• Maximum effect seen in 4-5 half-lifes
• Mostly in hepatic microsomal enzymes
  (mixed-function oxidases of cytochrome P450
  system)
• Other systems affected less well characterized
• Conjugation, acetylation, etc.
• P450 isoenzymes are variously affected.
• Most important with drugs with narrow TI, brittle
  hosts, agents with few alternate metabolic
  pathways
• Ex theophylline, antihypertensive agents,
  hypoglycemic agents, chemotherapeutic agents,
  some hormonal agents, HAART agents

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Pharmacokinetic Elimination - Metabolism

• Characteristics of interactions due to INCREASED
  metabolism
• Induction of metabolizing enzymes
• Timeframe is slow
• Recovery to basal state is also slow
• Mostly in hepatic microsomal enzymes but also in
  other tissues
• Clinical relevance is dependent upon timing of
  interaction, therapeutic index of affected drug,
  duration of therapy.
• Most frequently encountered inducing agents
• Phenobarbital, phenytoin, carbamazepine
• Rifampin gt rifabutin
• Cigarettes and charred or smoked foods
• Prolonged and substantial ethyl alcohol ingestion
• Isoniazid

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Mechanism of Induction of CYP3A4-Mediated
Metabolism of Drug Substrates (Panel A)

• The Resulting Reduced Plasma Drug Concentration
  (Panel B)
• Common Drug Substrates and Clinically Important
  Inhibitors of CYP2D6

Wilkinson, G. R. N Engl J Med 20053522211-2221
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Biotransformations

• Phase I
• Oxidation
• Cytochrome P450 monooxygenase system
• Flavin-containing monooxygenase system
• Alcohol dehydrogenase and aldehyde dehddrogenase
• Monoamine oxidase (Co-oxidation by peroxidases)
• Reduction
• NADPH-cytochrome P450 reductase
• Reduced (ferrous) cytochrome P450
• Hydroloysis
• Esterases amd amidases
• Epoxide hydrolase
• Phase II
• Glutathione S-transferases
• Mercapturic acid biosynthesis
• UDP-Glucoron(os)yltranasferases
• N-Acetyltransferases
• Amino acid N-acyl transferases
• Sulfotransferases

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Proportion of Drugs Metabolized by CYP450 Enzymes
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Cytochrome P450 3A4,5,7

• Largest number of drugs metabolized
• Present in the largest amount in the liver.
• Present in GI tract
• Not polymorphic
• Inherent activity varies widely, e.g. 1,000 fold
• Activity has been shown to predominate in the
  gut.
• Responsible for metabolism of
• Most calcium channel blockers
• Most benzodiazepines
• Most HIV protease inhibitors
• Most HMG-CoA-reductase inhibitors
• Cyclosporine
• Most non-sedating antihistamines
• Cisapride

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Cytochrome P450 3A4,5,7 -continued

• Substrates
• macrolide antibiotics clarithromycin,
  erythromycin benzodiazeines- diazepam,
  midazolam cyclosporine, tacrolimus, HIV
  Protease Inhibitors indinavir, ritonavir
  chlorpheniramine Calcium Channel Blockers
  nifedipine, amlodipine HMG Co A Reductase
  Inhibitors atorvastatin, lovastatin
  haloperidol, buspirone sildenafil, tamoxifen,
  trazodone, vincristine
• Inhibited by
• HIV Protease Inhibitors, cimetidine,
  clarithromycin, fluoxetine, fluvoxamine,
  grapefruit juice, itraconazole, ketoconazole,
  verapamil
• Induced by
• carbamazepine, phenobarbital, phenytoin,
  rifampin, St. Johns wort, troglitazone

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Cytochrome P450 2D6

• Second largest number of substrates.
• Polymorphic distribution
• Majority of the population is characterized as an
  extensive or even ultra-extensive metabolizer.
• Approximately 7 of the U.S. Caucasian population
  and 1-2 of African or Asian inheritance have a
  genetic defect in CYP2D6 that results in a poor
  metabolizer phenotype.
• Substrates include many b-blockers metoprolol,
  timolol, amitriptylline, imipramine, paroxetine,
  haloperidol, risperidone, thioridazine, codeine,
  dextromethorphan, ondansetron, tamoxifen,
  tramadol
• Inhibited by amiodarone, chlorpheniramine,
  cimetidine, fluoxetine, ritonavir

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Pharmacogenetics of Nortriptyline
Pharmacogenetics of Nortriptyline Variability of
CYP2D6 Expression
Weinshilboum, R. N Engl J Med 2003348529-537
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Pharmacogenetics of CYP2D6
Pharmacogenetics of CYP2D6
Weinshilboum, R. N Engl J Med 2003348529-537
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Cytochrome P450 2C9

• Note Absent in 1 of Caucasian and
  African-Americans.
• Substrates include many NSAIDs ibuprofen,
  tolbutamide, glipizide, irbesartan, losartan,
  celecoxib, fluvastatin, phenytoin,
  sulfamethoxazole, tamoxifen, tolbutamide,
  warfarin
• Inhibited by fluconazole, isoniazid, ticlopidine
• Induced by rifampin

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Cytochrome P450 1A2

• Substrates include caffeine, theophylline,
  imipramine, clozapine
• Inhibited by many fluoroquinolone antibiotics,
  fluvoxamine, cimetidine
• Induced by smoking tobacco

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(No Transcript)
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Cytochrome P450 2C19

• Note Absent in 20-30 of Asians, 3-5 of
  Caucasians
• Substrates include omeprazole, diazepam,
  phenytoin, phenobarbitone, amitriptylline,
  clomipramine, cyclophosphamide, progesterone
• Inhibited by fluoxetine, fluvoxamine,
  ketoconazole, lansoprazole, omeprazole,
  ticlopidine

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Cytochrome P450 2B6

• Substrates include bupropion, cyclophosphamide,
  efavirenz, methadone
• Inhibited by thiotepa
• Induced by phenobarbital, rifampin

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Cytochrome P450 2E1

• Substrates include acetaminophen

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Cytochrome P450 2C8

• Substrates paclitaxel, torsemide, amodiaquine,
  cerivastatin, repaglinide
• Inhibited by trimethoprim, quercetin,
  glitazones, gemfibrozil, montelukast
• Induced by rifampin

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The Usual Suspects - Inhibitors

• Amiodarone
• Ketoconazole
• Cimetidine
• Ciprofloxacin (1A2)
• Diltiazem
• Erythromycin (3A4)
• Ethanol (acute)
• Fluconazole (3A4)
• Fluoxetine (2C9, 2C19, 2D6)
• Fluvoxamine (1A2, 2C19, 3A4)
• Grapefruit (3A4)
• Isoniazid (2E1)

• Itraconazole (3A4)
• Ketaconazole (3A4)
• Metronidazole
• Miconazole (3A4)
• Nefazodone (3A4)
• Oral contraceptives
• Paroxetine (2D6)
• Phenylbutazone
• Quinidine (2D6)
• Sulfinpyrazone
• Valproate
• Verapamil

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The Usual Suspects - Inducers

• Barbiturates (2B)
• Carbamazepine (2C19, 3A4/5/7)
• Charcoal-broiled food (1A2)
• Dexamethasone
• Ethanol (chronic) (2E1)
• Griseofulvin

• Isoniazid (2E1)
• Primidone (2B)
• Rifabutin (3A4)
• Rifampin (2B6, 2CB, 2C19, 2C9, 2D6, 3A4/5/7)
• Tobacco smoke (1A2)

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Probe Substrates and Inhibitors for P450s
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Probe Substrates and Inhibitors for P450s
Substrates Substrates Inhibitors Inhibitors
P450 Preferred Acceptable Preferred Acceptable
CYP1A2 Ethoxyresorufin, phenacetin Caffeine (low turnover), theophylline (low turnover), acetanilide (mostly applied in hepatocytes), methoxyresorufin Furafylline a-Naphthoflavone (but coan also activate and inhibit CYP3A4)
CYP2A6 Coumarin Methoxypsoralen Coumarin (but high turnover), Sertraline (but also inhibits CYP2D6)
CYP2B6 S-Mephytoin (4-hydroxy metabolite) Ephenytoin (N-desmethyl metabolite) Bupropion (metabolite standards?)
CYP2C8 Glitazones (?)
CYP2C9
CYP2C19 S-Mephytoin (4-hydroxy metabolite), omeprazole Ticlopidine (but also inhibits CYP2D6), nootkatone (also inhibits CYP2A6)
CYP2D2 Bufuralol dextromethorphan Metoprolol, debrisoquine, codeine Quinidine
CYP2E1 Chlorzoxazone 4-Nitrophenol, lauric acid Clomethiazole 4-Methyl pyrazole
CYP3A Midazolam, testosterone (test at least 2) Nifedipine, felodipine, cyclosporin A, terfenadine, erythromycin, simvastatin Ketoconazole (not specific, also inhibits CYP2C8) Cyclosporin A
Adapted from Bjornsson TD, Callaghan JT , Einolf HJ, etal. Drug Met Disp 2003 31815-832 See also Tucker GT, Houston JB and Hyang SM. Pharm Res 2001 18 1071-1080. Adapted from Bjornsson TD, Callaghan JT , Einolf HJ, etal. Drug Met Disp 2003 31815-832 See also Tucker GT, Houston JB and Hyang SM. Pharm Res 2001 18 1071-1080. Adapted from Bjornsson TD, Callaghan JT , Einolf HJ, etal. Drug Met Disp 2003 31815-832 See also Tucker GT, Houston JB and Hyang SM. Pharm Res 2001 18 1071-1080. Adapted from Bjornsson TD, Callaghan JT , Einolf HJ, etal. Drug Met Disp 2003 31815-832 See also Tucker GT, Houston JB and Hyang SM. Pharm Res 2001 18 1071-1080. Adapted from Bjornsson TD, Callaghan JT , Einolf HJ, etal. Drug Met Disp 2003 31815-832 See also Tucker GT, Houston JB and Hyang SM. Pharm Res 2001 18 1071-1080. Adapted from Bjornsson TD, Callaghan JT , Einolf HJ, etal. Drug Met Disp 2003 31815-832 See also Tucker GT, Houston JB and Hyang SM. Pharm Res 2001 18 1071-1080.
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Drug Metabolism

• Phase I
• Oxidation
• Cytochrome P450 monooxygenase system
• Flavin-containing monooxygenase system
• Alcohol dehydrogenase and aldehyde dehddrogenase
• Monoamine oxidase (Co-oxidation by peroxidases)
• Reduction
• NADPH-cytochrome P450 reductase
• Reduced (ferrous) cytochrome P450
• Hydroloysis
• Esterases amd amidases
• Epoxide hydrolase
• Phase II
• Glutathione S-transferases
• UDP-Glucoron(os)yltranasferases
• N-Acetyltransferases
• Amino acid N-acyl transferases
• Sulfotransferases

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Monoamine Oxidase

• Many interactions
• 112 listed for Selegiline!
• May be very significant
• Used less frequently due to safer agents

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Relative Contribution to Drug Metabolism - Phase I
Evans Relling Science 1999
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Pharmacogenetics of Phase I Drug Metabolism
Weinshilboum, R. N Engl J Med 2003348529-537
59
Relative Contribution to Drug Metabolism - Phase
II
Evans Relling Science 1999
60
Pharmacogenetics of Phase II Drug Metabolism
Pharmacogenetics of Phase II Drug Metabolism
Weinshilboum, R. N Engl J Med 2003348529-537
61
Pharmacogenetics of Acetylation
Pharmacogenetics of Acetylation
Weinshilboum, R. N Engl J Med 2003348529-537
62
Drug Interactions Phase II

• Rarely rate-limiting step in either elimination
  or detoxification
• Phase I reactions increase polarity and excretion
  due to increased water solubility

63
Assessing the Clinical Relevance of CYP450 Drug
Interactions

1. Therapeutic Index and toxic potential of the
   substrate
2. Alternate pathways of metabolism
3. Role of active metabolites
4. Consequences of metabolic inhibition of
   metabolites
5. Are multiple P450s inhibited by inhibitor
6. Polymorphism of isoenzyme and patients
   metabolizer status
7. Inhibitory potential of metabolites
8. Is inhibition helpful or harmful

64
Mechanisms of Interactions

• Pharmacokinetic
• Absorption
• Distribution
• Metabolism
• Excretion

65
Pharmacokinetic Excretion

• Filtration
• Renally cleared drugs affected notably digoxin
  and aminoglycoside antibiotics
• Metabolic products of parent drug
• Highly dependent upon GFR of host, elderly of
  great concern
• Active secretion
• Two non-specific active transport systems (pars
  recta)
• Organic acids
• Organic bases
• Also digoxin in distal tubule
• Reabsorption
• Distal tubule and collecting duct
• Dependent on flow, pH
• Useful for enhancing excretion of selected agents
  with inhibition
• Probenecid, drug ingestions

66
Interactions Due to Altered Renal Excretion

• Drugs excreted by glomerular filtration unlikely
  to have significant interactions
• Drugs that are actively secreted into the tubular
  lumen can be inhibited by other drugs
• Sometimes useful
• Probenecid decreases Cl of penicillin
• Sometimes toxic
• Methotrexate secretion inhibited by aspirin
• Lithium carbonate excretion affected by total
  body Na balance
• Altered sodium balance thiazide and loop
  diuretics, some NSAIDs

67
Characterizing Drug Interactions

• Interacting agents
• Drug - Disease
• Drug-drug
• Prescription
• Non-prescription
• Illicit, recreational
• Food, supplements, herbal products

• Mechanism
• Pharmacodynamic
• Receptor inhibition
• Additive effects
• Pharmacokinetic
• Altered absorption, distribution, metabolism, or
  elimination

• Clinical Significance
• Major
• Substantial morbidity and mortality
• Therapy altering
• Manageable
• Little or no change in therapy
• Optimize therapy
• Intentional
• Additive or synergistic effects
• Enhanced pharmacokinetics

68
Drug-Disease Interactions

• Liver disease
• Renal disease
• Cardiac disease (hepatic blood flow)
• Acute myocardial infarction?
• Acute viral infection?
• Hypothyroidism or hyperthyroidism?
• SIRS ?

69
Drug-Food Interactions

• Tetracycline and milk products
• Warfarin and vitamin K-containing foods
• Grapefruit juice
• Effects of grapefruit juice on felodipine
  pharmacokinetics and pharmacodynamics.

70
Effects of grapefruit juice on felodipine
pharmacokinetics and pharmacodynamics
Dresser GK et al Clin Pharmacol Ther
200068(1)2834
71
Drug-Herbal Interactions

• St. Johns wort with indinavir
• St. Johns wort with cyclosporin
• St. Johns wort with digoxin?
• Many others

72
After St. Johns wort
73
Prediction of Drug Interactions, In vitro

• In Vitro Screening
• Non-mammalian in vivo systems have very limited
  clinical utility
• In vitro systems to screen for CYP450-mediated
  drug interactions include microsomes,
  hepatocytes, liver slices, purified P450 systems,
  and recombinant human P450 enzymes.
• Most useful for screening inhibitory effects.
• Less useful for drugs with multiple metabolic
  pathways.
• Least useful for studying induction.
• Unknown appropriate concentration of inhibitor in
  vitro that would correlate with in vivo exposure.
• Utility in guiding subsequent clinical trials

74
In Vivo Drug-Drug Interaction Studies

• Pharmacokinetic interactions must be evaluated
  relative to clinical relevance.
• Studies should be used for OPI
• Study design dictated by clinical objective (ex.
  cross-over versus parallel)
• Chronic versus acute dosing
• Sequence
• Relevant concentrations
• Steady-state versus acute short interval
• Endpoints (pharmacokinetic vs. pharmacodynamic)
• Sample size, statistical considerations
• Demonstration of Lack of effect vs. Magnitude
  of effect

75
In Vivo Drug-Drug Interaction Studies, contd.

• Study populations
• Population pharmacokinetic approach
• In vitro characterization of likely targets
• Subgroups
• Safety concerns
• Clinical trials
• Concurrent pharmacokinetic studies
• Case Reports

76
Prediction of Drug Interactions, Resources

• Clinical Trials
• CDER Guidance for Industry http//0-www.fda.gov.l
  ilac.une.edu/cder/guidance/clin3.pdf
• The Conduct of In Vitro and In Vivo Drug-Drug
  Interaction Studies A Pharmaceutical Research
  and Manufacturers of America (PhRMA) Perspective.
  TD Bjornsson, and Others. Drug Met Disp 2003 31
  815-832.
• Case Reports MedWatch _at_ FDA

77
General Approach to Managing Drug Interactions

• Each contact with the patient includes a review
  of all medications - prescribed and OTC.
• Information on medications prescribed by any and
  all health-care providers is reviewed
• Specifically query for problematic food and
  nutriceutical products
• Keep a high Index of Suspicion for all toxic
  events and therapeutic failures
• When possible, use agents which are the least
  problematic
• Sometimes, timing of doses may minimize
  interactions, especially with food
• Proactively instruct patients about avoiding
  interactions
• Usually, management of interactions requires
  minimal alterations in therapeutic plan

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Conclusions

• Drug-drug interactions are part of drug therapy
• May be beneficial or hazardous
• Polypharmacy (therapy with many agents) is often
  unavoidable
• Estimated that for 5 or more agents the
  probability of interaction approaches 100
• Managing drug interactions is often more
  important than avoiding
• Be most cautious with narrow TI agents
• Make use of resources
• Some interactions are absolutely contraindicated
• Drug interactions are significant cause of
  adverse drug events and cost billions in
  additional health care costs.
• At-risk patients are most affected, e.g. the
  elderly, the very young, the critically ill.

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Summary Drug Interactions

• Pharmacokinetic drug interactions are defined as
  those that alter drug absorption, distribution,
  metabolism, or excretion.
• Pharmacodynamic drug interactions result in an
  alteration of the biochemical or physiological
  effects of a drug. Interactions of this type are
  more difficult to characterize than
  pharmacokinetic interactions.

80
Summary Drug Interactions

• Drug interactions that alter the rate of
  absorption are usually of lesser concern that
  those that affect the extent.
• Overall outcomes of interactions of agonists and
  antagonists at the drug receptor are dependent on
  the varying affinities and activities of the
  different agents involved.

81
Summary Drug Interactions

• Alteration of metabolism of drugs in the liver,
  gut and other sites is an important but not
  singular source of significant drug interactions.
• In general, those drugs that are susceptible to
  the effects of induction of metabolism are also
  subject to inhibition.
• Drug interactions involving induction of
  metabolism develop more slowly than those
  involving inhibition.

82
Summary Drug Interactions

• A full profile of the interaction potential of
  any given drug generally takes an extended amount
  of time in the marketplace to be characterized.
  Many, but not all, important drug interactions
  are described in the official labeling.

83
Summary Drug Metabolism

• Polymorphism of CYP gene(s) can result in a poor
  metabolizer phenotype, but occurs in less than
  20 of the U.S. general population.
• Prototypic inhibiting agents include
• Ciprofloxacin, Erythromycin, Fluconazole,
  Fluoxetine, Grapefruit juice, Itraconazole
• Prototypic inducing agents include
• Carbamazepine (2C19, 3A4/5/7)
• Rifampin (2B6, 2CB, 2C19, 2C9, 2D6, 3A4/5/7)

84
Questions?

• Blair Holbein, Ph.D.
• Presbyterian Hospital of Dallas
• Email bholbein_at_hcin.net
• Website http//phdres.caregate.net
• Annotated bibliography
• Slides