drug interactions clinical pharmacology spring course 2006 m. e. blair holbein, ph.d. clinical...

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


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


Pharmacodynamic

Receptor

Non-receptor

Pharmacokinetic

Absorption

Distribution

Metabolism

Excretion


Pharmacokinetic

Absorption

Distribution

Metabolism

Excretion


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


Some Common Drugs with Low Oral Bioavailability and Susceptibility to First-Pass Drug Interactions


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


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


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


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


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)

http://medicine.iupui.edu/flockhart/


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


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


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


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


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


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

http://www.sciencemag.org/cgi/content/full/286/5439/487?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=relling&searchid=1114544535046_9445&stored_search=&FIRSTINDEX=0




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 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


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

http://0-www.fda.gov.lilac.une.edu/cder/guidance/clin3.pdf

http://dmd.aspetjournals.org/cgi/content/abstract/31/7/815



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.


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.


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: [email protected] Website: http://phdres.caregate.net Annotated bibliography Slides

mailto:[email protected]

http://phdres.caregate.net/

drug interactions clinical pharmacology spring course 2006 m. e. blair holbein, ph.d. clinical...

Documents

drug receptoractivity

adr patients

elderly patients

reduced toxicity

serious adrs

deaths yearly adrs

synergistic combinations

cost reduction