Post on 13-Jan-2016
Drug InteractionsClinical Pharmacology
Spring Course 2006
M. E. Blair Holbein, Ph.D.
Clinical Pharmacologist
Presbyterian Hospital
Why study drug interactions?Why study drug interactions?Why study drug interactions?Why study drug interactions?
Ref: Institute of Medicine, National Academy Press, 2000, Lazarou J et al. JAMA 1998;279(15):1200–1205, Gurwitz JH et al. Am J Med 2000;109(2):87–94.Johnson JA et al. Arch Intern Med 1995;155(18):1949–1956, Leape LL et al. N Engl J Med 1991;324(6):377–384, Classen DC et al. JAMA 1997;277(4):301–306
Clinical Significance of Drug InteractionsClinical Significance of Drug InteractionsClinical Significance of Drug InteractionsClinical 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 rate—50,000 yearly Ambulatory patients ADR rate—unknown Many clinical implications
Libby Zion case Clinical Trials, OPI International Intrigue?
erererer
PreventablePreventable drug interactions drug interactionsPreventablePreventable drug interactions drug interactions
1/3 of adverse drug events
and 1/2 cost.
Wright JM. 2000. Drug Interactions. In: Carruthers SG, Hoffman BB, et al. , ed. Melmon and Morrelli’s Clinical Pharmacology: Basic Principles in Therapeutics, 4th ed. New York:McGraw-Hill.
Definition Definition Definition 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 efficacyMay be beneficial: synergistic combinations,
pharmacokinetic boosting, increased convenience, reduced toxicity, cost reduction .
Characterizing Drug InteractionsCharacterizing Drug InteractionsCharacterizing Drug InteractionsCharacterizing 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
Mechanisms of InteractionsMechanisms of InteractionsMechanisms of InteractionsMechanisms of Interactions
Pharmacodynamic
Receptor
Non-receptor
Pharmacokinetic
Absorption
Distribution
Metabolism
Excretion
Mechanisms of InteractionsMechanisms of InteractionsMechanisms of InteractionsMechanisms of Interactions
Pharmacodynamic
Receptor
Non-receptor
Pharmacodynamic: PharmacologicalPharmacodynamic: PharmacologicalPharmacodynamic: PharmacologicalPharmacodynamic: Pharmacological
Interaction at the drug receptor Activity is function of intrinsic activity and affinity for
receptorAgonist and antagonists
Effect also function of concentration at receptor
Effect can be additiveSeveral 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.
Pharmacodynamic: PhysiologicalPharmacodynamic: PhysiologicalPharmacodynamic: PhysiologicalPharmacodynamic: Physiological
Agents that can act in concert or in opposition via different cellular mechanisms.Both theophylline and -receptor agonists can cause
bronchiolar muscle relaxationSensitization of myocardium to arrhythmogenic action
of catecholamines by general anesthetics.Combinations of antihypertensive (can be intentional)
Pharmacodynamic: Altered physiologyPharmacodynamic: Altered physiologyPharmacodynamic: Altered physiologyPharmacodynamic: Altered physiology
Altered cellular environmentAging effects
Blunted sympathetic nervous system; blunted responses
Agents that change the state of the hostEx. Hypokalemia caused by diuretics increases toxicity of
digoxin.
Pharmacodynamic: NeutralizationPharmacodynamic: NeutralizationPharmacodynamic: NeutralizationPharmacodynamic: Neutralization
Neutralization systemically in the host (as opposed to prior to absorption)Protamine used to neutralize heparinPurified antidigoxin Fab fragments used to treat
digoxin toxicity
Mechanisms of InteractionsMechanisms of InteractionsMechanisms of InteractionsMechanisms of Interactions
Pharmacodynamic
Receptor
Non-receptor
Pharmacokinetic
Absorption
Distribution
Metabolism
Excretion
Mechanisms of InteractionsMechanisms of InteractionsMechanisms of InteractionsMechanisms of Interactions
Pharmacokinetic
Absorption
Distribution
Metabolism
Excretion
Mechanisms of InteractionsMechanisms of InteractionsMechanisms of InteractionsMechanisms of Interactions
Pharmacokinetic
AbsorptionDistribution
Metabolism
Excretion
Pharmacokinetic: AbsorptionPharmacokinetic: AbsorptionPharmacokinetic: AbsorptionPharmacokinetic: Absorption
Alters rate that drug enters the system with altered level or time to peak
Mechanisms:Physical interaction, chelation, binding. e.g. tetracyclines and
cationsAltered GI function: changes in pH (ketoconazole), motility,
mucosal function, metabolism, absorption sites, perfusion
Absorption: in the gutAbsorption: in the gutAbsorption: in the gutAbsorption: 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
Interactions: Presystemic EliminationInteractions: Presystemic EliminationInteractions: Presystemic EliminationInteractions: Presystemic Elimination
Gut transit and metabolism Intestinal wall CYP3A4 metabolizes a number of drugs Inhibition/induction results in altered bioavailabilityEx: 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
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by Felodipine and Its Interaction with Grapefruit JuiceFelodipine and Its Interaction with Grapefruit Juice
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
Some Common Drugs with Low Oral Bioavailability and Susceptibility to First-Pass Drug Interactions
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
Consequences of the Inhibition of First-Pass Metabolism, as Exemplified by the Interaction between Felodipine and Grapefruit Juice
Induction of P-glycoprotein and Intestinal CYP450Induction of P-glycoprotein and Intestinal CYP450Induction of P-glycoprotein and Intestinal CYP450Induction of P-glycoprotein and Intestinal CYP450
Intestinal epithelium with CYP450Sufficient amout to result in presystemic clearance of some
drugsHighly variable
Enterocytes have transporter proteinsOrganic 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
Intestinal Transporter - P-glycoproteinIntestinal Transporter - P-glycoproteinIntestinal Transporter - P-glycoproteinIntestinal Transporter - P-glycoprotein
P-glycoprotein Substrates and Inhibitors
Substrates InhibitorsActinomycinAmprenavirColchicinesCortisolCyclosporineDaunorubicinDexamethasoneDigoxinDiltiazemDocetaxelDoxorubicinErythromycinEtoposideFexofenadineHydrocortisoneIndinavirIvermectinLoperamideMitomycin C
MitoxantroneMorphineNelfinavirNicardipineNifedipinePaclitaxelProgesteroneRifampinRitonavirSaquinavirTacrolimusTaxolTeniposideTopotecanVerapamilVinblastineVincristine
AmiodaroneBepridilCefoperzoneCeftriaxoneClarithromycinCortisolCyclosporineDiltiazemDipyridamoleErythromycinItraconazoleFelodipineFluperazineHydrocortisoneKetoconazoleLidocaine
MefloquineNicardipineNifedipineNitrendipineProgesteronePropranololQuercetinQuinineQuinidineReserpineTacrolimusTamoxifenTestosteroneTrifluoperaineVerapamil
Intestinal Monoamine OxidaseIntestinal Monoamine OxidaseIntestinal Monoamine OxidaseIntestinal 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
Mechanisms of InteractionsMechanisms of InteractionsMechanisms of InteractionsMechanisms of Interactions
Pharmacokinetic
Absorption
DistributionMetabolism
Excretion
Pharmacokinetic: DistributionPharmacokinetic: DistributionPharmacokinetic: DistributionPharmacokinetic: 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 capacityhypoalbuminemia (acidic drugs)1-acid glycoprotein (basic drugs) acute phase reactants
Pharmacokinetic: DistributionPharmacokinetic: DistributionPharmacokinetic: DistributionPharmacokinetic: 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
Pharmacokinetic: DistributionPharmacokinetic: DistributionPharmacokinetic: DistributionPharmacokinetic: 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 PGPSome correlation with CYP3A4 affinities
May be significant for some anticancer drugs
Mechanisms of InteractionsMechanisms of InteractionsMechanisms of InteractionsMechanisms of Interactions
Pharmacokinetic
Absorption
Distribution
MetabolismExcretion
Drug MetabolismDrug MetabolismDrug MetabolismDrug Metabolism
Phase I Oxidation
Cytochrome P450 monooxygenase systemFlavin-containing monooxygenase systemAlcohol dehydrogenase and aldehyde dehyddrogenaseMonoamine oxidase (Co-oxidation by peroxidases)
ReductionNADPH-cytochrome P450 reductaseReduced (ferrous) cytochrome P450
HydroloysisEsterases amd amidasesEpoxide hydrolase
Phase II Glutathione S-transferases UDP-Glucoron(os)yltranasferases N-Acetyltransferases Amino acid N-acyl transferases Sulfotransferases
Interactions in the Phases of Drug MetabolismInteractions in the Phases of Drug MetabolismInteractions in the Phases of Drug MetabolismInteractions 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 CYP2D6—can 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 isozymeImipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19If co-administered with CYP450 inhibitor, some isozymes may “pick up slack”
for inhibited isozyme. Drugs may be metabolized by a combination of enzymatic systems.
Pharmacokinetic: Elimination - MetabolismPharmacokinetic: Elimination - MetabolismPharmacokinetic: Elimination - MetabolismPharmacokinetic: 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
SubstratesInhibiting agentsInducing agents
No consistent correlation of substrate versus inhibitor or inducer Good reference: http://medicine.iupui.edu/flockhart/ (alias: www.drug-
interactions.com)
Pharmacokinetic: Elimination - MetabolismPharmacokinetic: Elimination - MetabolismPharmacokinetic: Elimination - MetabolismPharmacokinetic: Elimination - Metabolism
Characteristics of interactions with DECREASED metabolism
Inhibition of metabolizing enzymesTimeframe is rapidDuration 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
Pharmacokinetic: Elimination - MetabolismPharmacokinetic: Elimination - MetabolismPharmacokinetic: Elimination - MetabolismPharmacokinetic: Elimination - Metabolism
Characteristics of interactions due to INCREASED metabolism
Induction of metabolizing enzymesTimeframe is slow “Recovery” to basal state is also slowMostly 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, carbamazepineRifampin > rifabutinCigarettes and charred or smoked foodsProlonged and substantial ethyl alcohol ingestion Isoniazid
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
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
BiotransformationsBiotransformationsBiotransformationsBiotransformations
Phase I Oxidation
Cytochrome P450 monooxygenase systemFlavin-containing monooxygenase systemAlcohol dehydrogenase and aldehyde dehddrogenaseMonoamine oxidase (Co-oxidation by peroxidases)
ReductionNADPH-cytochrome P450 reductaseReduced (ferrous) cytochrome P450
HydroloysisEsterases amd amidasesEpoxide hydrolase
Phase II Glutathione S-transferases Mercapturic acid biosynthesis UDP-Glucoron(os)yltranasferases N-Acetyltransferases Amino acid N-acyl transferases Sulfotransferases
Proportion of Drugs Metabolized by CYP450 EnzymesProportion of Drugs Metabolized by CYP450 EnzymesProportion of Drugs Metabolized by CYP450 EnzymesProportion of Drugs Metabolized by CYP450 Enzymes
CYP2C198%
CYP1A211%
CYP2A63%
CYP2C916%
CYP2E14%
CYP3A438%
CYP2D620%
Cytochrome P450 3A4,5,7Cytochrome P450 3A4,5,7Cytochrome P450 3A4,5,7Cytochrome 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 blockersMost benzodiazepinesMost HIV protease inhibitorsMost HMG-CoA-reductase inhibitorsCyclosporineMost non-sedating antihistaminesCisapride
Cytochrome P450 3A4,5,7 -continuedCytochrome P450 3A4,5,7 -continuedCytochrome P450 3A4,5,7 -continuedCytochrome 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. John’s
wort, troglitazone
Cytochrome P450 2D6Cytochrome P450 2D6Cytochrome P450 2D6Cytochrome 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 -blockers – metoprolol, timolol, amitriptylline, imipramine, paroxetine, haloperidol, risperidone, thioridazine, codeine, dextromethorphan, ondansetron, tamoxifen, tramadol
Inhibited by: amiodarone, chlorpheniramine, cimetidine, fluoxetine, ritonavir
Pharmacogenetics of Nortriptyline
Pharmacogenetics of Nortriptyline
Weinshilboum, R. N Engl J Med 2003;348:529-537
Pharmacogenetics of NortriptylineVariability of CYP2D6 Expression
Pharmacogenetics of CYP2D6Pharmacogenetics of CYP2D6
Weinshilboum, R. N Engl J Med 2003;348:529-537
Pharmacogenetics of CYP2D6
Cytochrome P450 2C9Cytochrome P450 2C9Cytochrome P450 2C9Cytochrome 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
Cytochrome P450 1A2Cytochrome P450 1A2Cytochrome P450 1A2Cytochrome P450 1A2
Substrates include: caffeine, theophylline, imipramine, clozapine
Inhibited by: many fluoroquinolone antibiotics, fluvoxamine, cimetidine
Induced by: smoking tobacco
Cytochrome P450 2C19Cytochrome P450 2C19Cytochrome P450 2C19Cytochrome 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
Cytochrome P450 2B6Cytochrome P450 2B6Cytochrome P450 2B6Cytochrome P450 2B6
Substrates include: bupropion, cyclophosphamide, efavirenz, methadone
Inhibited by: thiotepa Induced by: phenobarbital, rifampin
Cytochrome P450 2E1Cytochrome P450 2E1Cytochrome P450 2E1Cytochrome P450 2E1
Substrates include: acetaminophen
Cytochrome P450 2C8Cytochrome P450 2C8Cytochrome P450 2C8Cytochrome P450 2C8
Substrates; paclitaxel, torsemide, amodiaquine, cerivastatin, repaglinide
Inhibited by: trimethoprim, quercetin, glitazones, gemfibrozil, montelukast
Induced by: rifampin
The “Usual Suspects” - InhibitorsThe “Usual Suspects” - InhibitorsThe “Usual Suspects” - InhibitorsThe “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
The “Usual Suspects” - InducersThe “Usual Suspects” - InducersThe “Usual Suspects” - InducersThe “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)
Probe Substrates and Inhibitors for P450sProbe Substrates and Inhibitors for P450sProbe Substrates and Inhibitors for P450sProbe Substrates and Inhibitors for P450s
Substrates InhibitorsP450 Preferred Acceptable Preferred Acceptable
CYP1A2 Ethoxyresorufin,phenacetin
Caffeine (low turnover),theophylline (low turnover),acetanilide (mostly applied inhepatocytes),methoxyresorufin
Furafyllinea-Naphthoflavone (butcoan also activate andinhibit CYP3A4)
CYP2A6 Coumarin 8-MethoxypsoralenCoumarin (but highturnover), Sertraline (butalso inhibits CYP2D6)
CYP2B6 S-Mepheytoin (N-desmethyl metabolite)
Ephenytoin (N-desmethylmetabolite)
Bupropion (metabolitestandards?)
CYP2C8 Paclitxel (?) Glitazones (?)
CYP2C9 S-Warfarin,diclofenac
Tobutamine (low turnover) Sulphaphenazole
CYP2C19S-Mephytoin (4-hydroxy metabolite),omeprazole
Ticlopidine (but alsoinhibits CYP2D6),nootkatone (also inhibitsCYP2A6)
CYP2D6 Bufuraloldextromethorphan
Metoprolol, debrisoquine,codeine
Quinidine
CYP2E1 Chlorzoxazone 4-Nitrophenol, lauric acid Clomethiazole 4-Methyl pyrazole
CYP3AMidazolam,testosterone (test atleast 2)
Nifedipine, felodipine,cyclosporin A, terfenadine,erythromycin, simvastatin
Ketoconazole (notspecific, slo inhibitsCYP2C8)
Cyclosporin A
Adapted from Bjornsson TD, Callaghan JT , Einolf HJ, etal. Drug Met Disp 2003; 31:815-832; See also Tucker GT, Houston JB andHyang SM. Pharm Res 2001; 18: 1071-1080.
Probe Substrates and Inhibitors for P450sProbe Substrates and Inhibitors for P450sProbe Substrates and Inhibitors for P450sProbe Substrates and Inhibitors for P450s
Substrates 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; 31:815-832; See also Tucker GT, Houston JB and Hyang SM. Pharm Res 2001; 18: 1071-1080.
Drug MetabolismDrug MetabolismDrug MetabolismDrug 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
Monoamine OxidaseMonoamine OxidaseMonoamine OxidaseMonoamine Oxidase
Many interactions112 listed for Selegiline!
May be very significant Used less frequently due to safer agents
Relative Contribution to Drug Metabolism - Phase IRelative Contribution to Drug Metabolism - Phase IRelative Contribution to Drug Metabolism - Phase IRelative Contribution to Drug Metabolism - Phase I
Evans & Relling Science 1999
Weinshilboum, R. N Engl J Med 2003;348:529-537
Pharmacogenetics of Phase I Drug Metabolism
Relative Contribution to Drug Metabolism - Phase IIRelative Contribution to Drug Metabolism - Phase IIRelative Contribution to Drug Metabolism - Phase IIRelative Contribution to Drug Metabolism - Phase II
Evans & Relling Science 1999
Pharmacogenetics of Phase II Drug Metabolism
Pharmacogenetics of Phase II Drug Metabolism
Weinshilboum, R. N Engl J Med 2003;348:529-537
Pharmacogenetics of Phase II Drug Metabolism
Pharmacogenetics of Acetylation
Pharmacogenetics of Acetylation
Weinshilboum, R. N Engl J Med 2003;348:529-537
Pharmacogenetics of Acetylation
Drug Interactions: Phase IIDrug Interactions: Phase IIDrug Interactions: Phase IIDrug Interactions: Phase II
Rarely rate-limiting step in either elimination or detoxification
Phase I reactions increase polarity and excretion due to increased water solubility
Assessing the Clinical Relevance of CYP450 Drug Assessing the Clinical Relevance of CYP450 Drug InteractionsInteractionsAssessing the Clinical Relevance of CYP450 Drug Assessing the Clinical Relevance of CYP450 Drug InteractionsInteractions
1. Therapeutic Index and toxic potential of the substrate
2. Alternate pathways of metabolism3. Role of active metabolites4. Consequences of metabolic inhibition of
metabolites5. Are multiple P450s inhibited by inhibitor6. Polymorphism of isoenzyme and patient’s
metabolizer status7. Inhibitory potential of metabolites8. Is inhibition helpful or harmful
Mechanisms of InteractionsMechanisms of InteractionsMechanisms of InteractionsMechanisms of Interactions
Pharmacokinetic
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetic: ExcretionPharmacokinetic: ExcretionPharmacokinetic: ExcretionPharmacokinetic: Excretion
FiltrationRenally cleared drugs affected notably digoxin and
aminoglycoside antibioticsMetabolic products of parent drugHighly dependent upon GFR of host, elderly of great concern
Active secretionTwo non-specific active transport systems (pars recta)
Organic acidsOrganic bases
Also digoxin in distal tubule Reabsorption
Distal tubule and collecting duct Dependent on flow, pHUseful for enhancing excretion of selected agents with inhibition
Probenecid, drug ingestions
Interactions Due to Altered Renal ExcretionInteractions Due to Altered Renal ExcretionInteractions Due to Altered Renal ExcretionInteractions 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 drugsSometimes useful:
Probenecid decreases Cl of penicillinSometimes toxic
Methotrexate secretion inhibited by aspirinLithium carbonate excretion affected by total body Na balance
Altered sodium balance: thiazide and loop diuretics, some NSAIDs
Characterizing Drug InteractionsCharacterizing Drug InteractionsCharacterizing Drug InteractionsCharacterizing Drug Interactions
Mechanism Pharmacodynamic
Receptor inhibition Additive effects
Pharmacokinetic Altered absorption, distribution,
metabolism, or elimination
Interacting agents Drug - Disease Drug-drug
PrescriptionNon-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
Drug-Disease InteractionsDrug-Disease InteractionsDrug-Disease InteractionsDrug-Disease Interactions
Liver disease Renal disease Cardiac disease (hepatic blood flow) Acute myocardial infarction? Acute viral infection? Hypothyroidism or hyperthyroidism? SIRS ?
Drug-Food InteractionsDrug-Food InteractionsDrug-Food InteractionsDrug-Food Interactions
Tetracycline and milk products Warfarin and vitamin K-containing foods Grapefruit juice
Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics.
Dresser GK et al Clin Pharmacol Ther 2000;68(1):28–34
Effects of grapefruit juice on felodipine pharmacokinetics and Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamicspharmacodynamics
Effects of grapefruit juice on felodipine pharmacokinetics and Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamicspharmacodynamics
Drug-Herbal InteractionsDrug-Herbal InteractionsDrug-Herbal InteractionsDrug-Herbal Interactions
St. John’s wort with indinavir St. John’s wort with cyclosporin St. John’s wort with digoxin? Many others
After St. John’s wort
Prediction of Drug Interactions, Prediction of Drug Interactions, In vitroIn vitroPrediction of Drug Interactions, Prediction of Drug Interactions, In vitroIn 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
In VivoIn Vivo Drug-Drug Interaction Studies Drug-Drug Interaction StudiesIn VivoIn Vivo Drug-Drug Interaction Studies Drug-Drug Interaction Studies
Pharmacokinetic interactions must be evaluated relative to clinical relevance.Studies should be used for OPIStudy design dictated by clinical objective (ex. cross-over versus
parallel)Chronic versus acute dosingSequenceRelevant concentrationsSteady-state versus acute short intervalEndpoints (pharmacokinetic vs. pharmacodynamic)Sample size, statistical considerationsDemonstration of “Lack of effect” vs. “Magnitude of effect”
In VivoIn Vivo Drug-Drug Interaction Studies, cont’d. Drug-Drug Interaction Studies, cont’d.In VivoIn Vivo Drug-Drug Interaction Studies, cont’d. Drug-Drug Interaction Studies, cont’d.
Study populationsPopulation pharmacokinetic approach In vitro characterization of likely targetsSubgroupsSafety concerns
Clinical trialsConcurrent pharmacokinetic studies
Case Reports
Prediction of Drug Interactions, ResourcesPrediction of Drug Interactions, ResourcesPrediction of Drug Interactions, ResourcesPrediction of Drug Interactions, Resources
Clinical TrialsCDER Guidance for Industry [http://0-
www.fda.gov.lilac.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 @ FDA
General Approach to Managing Drug InteractionsGeneral Approach to Managing Drug InteractionsGeneral Approach to Managing Drug InteractionsGeneral 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
ConclusionsConclusionsConclusionsConclusions
Drug-drug interactions are part of drug therapyMay be beneficial or hazardousPolypharmacy (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 avoidingBe most cautious with narrow TI agents Make use of resourcesSome 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.
Summary: Drug InteractionsSummary: Drug InteractionsSummary: Drug InteractionsSummary: 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.
Summary: Drug InteractionsSummary: Drug InteractionsSummary: Drug InteractionsSummary: 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.
Summary: Drug InteractionsSummary: Drug Interactions Summary: Drug InteractionsSummary: 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.
Summary: Drug InteractionsSummary: Drug InteractionsSummary: Drug InteractionsSummary: 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.
Summary Drug MetabolismSummary Drug MetabolismSummary Drug MetabolismSummary 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)
Questions?Questions?Questions?Questions?
Blair Holbein, Ph.D.Presbyterian Hospital of Dallas
Email: bholbein@hcin.net Website: http://phdres.caregate.net Annotated bibliography Slides