Drug Interactions
Clinical Pharmacology
Spring Course 2006
M. E. Blair Holbein, Ph.D.
Clinical Pharmacologist
Presbyterian Hospital
Why study drug interactions?
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 rate—50,000 yearly
Ambulatory patients ADR rate—unknown
Many clinical implications
 Libby
Zion case
 Clinical Trials, OPI
 International Intrigue?
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
er
Preventable drug interactions
1/3
of adverse drug events
and
1/2 cost.
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 Morrelli’s Clinical Pharmacology: Basic
Principles in Therapeutics, 4th ed. New York:McGraw-Hill.
Characterizing Drug Interactions
Mechanism

Interacting agents
Pharmacodynamic
Receptor inhibition
 Additive effects



Drug - Disease

Drug-drug
Pharmacokinetic

Altered absorption, distribution,
metabolism, or elimination


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 Interactions
Pharmacodynamic
Pharmacokinetic
Receptor
Absorption
Non-receptor
Distribution
Metabolism
Excretion
Mechanisms of Interactions
Pharmacodynamic
Receptor
Non-receptor
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.
Pharmacodynamic: Physiological
 Agents
that can act in concert or in opposition
via different cellular mechanisms.
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)
Both
Pharmacodynamic: Altered physiology
 Altered
Aging
cellular environment
effects
Blunted sympathetic nervous system; blunted responses
Agents
that change the state of the host
Ex. Hypokalemia caused by diuretics increases toxicity of
digoxin.
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
Mechanisms of Interactions
Pharmacodynamic
Pharmacokinetic
Receptor
Absorption
Non-receptor
Distribution
Metabolism
Excretion
Mechanisms of Interactions
Pharmacokinetic
Absorption
Distribution
Metabolism
Excretion
Mechanisms of Interactions
Pharmacokinetic
Absorption
Distribution
Metabolism
Excretion
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
Absorption: in the gut
Sucralfate, some milk products,
antacids, and oral iron
preparations
Block absorption of quinolones,
tetracycline, and azithromycin
Omeprazole, lansoprazole,
H2-antagonists
Reduce absorption of
ketoconazole, delavirdine
Didanosine (given
as a buffered tablet)
Reduces ketoconazole
absorption
Cholestyramine
Binds raloxifene,thyroid
hormone, and digoxin
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
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 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
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
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
Intestinal Transporter - P-glycoprotein
P-glycoprotein Substrates and Inhibitors
Substrates
Actinomycin
Amprenavir
Colchicines
Cortisol
Cyclosporine
Daunorubicin
Dexamethasone
Digoxin
Diltiazem
Docetaxel
Doxorubicin
Erythromycin
Etoposide
Fexofenadine
Hydrocortisone
Indinavir
Ivermectin
Loperamide
Mitomycin C
Inhibitors
Mitoxantrone
Morphine
Nelfinavir
Nicardipine
Nifedipine
Paclitaxel
Progesterone
Rifampin
Ritonavir
Saquinavir
Tacrolimus
Taxol
Teniposide
Topotecan
Verapamil
Vinblastine
Vincristine
Amiodarone
Bepridil
Cefoperzone
Ceftriaxone
Clarithromycin
Cortisol
Cyclosporine
Diltiazem
Dipyridamole
Erythromycin
Itraconazole
Felodipine
Fluperazine
Hydrocortisone
Ketoconazole
Lidocaine
Mefloquine
Nicardipine
Nifedipine
Nitrendipine
Progesterone
Propranolol
Quercetin
Quinine
Quinidine
Reserpine
Tacrolimus
Tamoxifen
Testosterone
Trifluoperaine
Verapamil
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
Mechanisms of Interactions
Pharmacokinetic
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetic: Distribution
 Protein-binding
 Relative
displacement
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
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
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
Mechanisms of Interactions
Pharmacokinetic
Absorption
Distribution
Metabolism
Excretion
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
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 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 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.
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/flockhart/ (alias: www.druginteractions.com)
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
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 > rifabutin
Cigarettes and charred or smoked foods
Prolonged and substantial ethyl alcohol ingestion
Isoniazid
Mechanism of Induction of
CYP3A4-Mediated Metabolism of
Drug Substrates (Panel A)
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
The Resulting Reduced Plasma
Drug Concentration (Panel B)
Common
CYP2D6
Drug Substrates and Clinically Important Inhibitors of
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

Proportion of Drugs Metabolized by CYP450 Enzymes
CYP2D6
20%
CYP3A4
38%
CYP2C19
8%
CYP1A2
11%
CYP2C9
16%
CYP2E1
4%
CYP2A6
3%
Cytochrome P450 3A4,5,7
 Largest
number of drugs metabolized
 Present in the largest amount in the liver.
Present
 Not
in GI tract
polymorphic
Inherent
activity varies widely, e.g. 1,000 fold
Activity has been shown to predominate in the gut.
 Responsible
Most
for metabolism of:
calcium channel blockers
Most benzodiazepines
Most HIV protease inhibitors
Most HMG-CoA-reductase inhibitors
Cyclosporine
Most non-sedating antihistamines
Cisapride
Cytochrome P450 3A4,5,7 -continued
 Substrates:
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
macrolide
 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 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.
include: many b-blockers – metoprolol,
timolol, amitriptylline, imipramine, paroxetine,
haloperidol, risperidone, thioridazine, codeine,
dextromethorphan, ondansetron, tamoxifen, tramadol
 Inhibited by: amiodarone, chlorpheniramine, cimetidine,
fluoxetine, ritonavir
 Substrates
Pharmacogenetics of Nortriptyline
Variability of CYP2D6 Expression
Pharmacog
enetics of
Nortriptylin
e
Weinshilboum, R. N Engl J Med 2003;348:529-537
Pharmacogenetics of CYP2D6
Pharmacogenetics of CYP2D6
Weinshilboum, R. N Engl J Med 2003;348:529-537
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
Cytochrome P450 1A2
 Substrates
include: caffeine, theophylline, imipramine,
clozapine
 Inhibited by: many fluoroquinolone antibiotics,
fluvoxamine, cimetidine
 Induced by: smoking tobacco
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
Cytochrome P450 2B6
 Substrates
include: bupropion, cyclophosphamide,
efavirenz, methadone
 Inhibited by: thiotepa
 Induced by: phenobarbital, rifampin
Cytochrome P450 2E1
 Substrates
include: acetaminophen
Cytochrome P450 2C8
 Substrates;
paclitaxel, torsemide, amodiaquine,
cerivastatin, repaglinide
 Inhibited by: trimethoprim, quercetin, glitazones,
gemfibrozil, montelukast
 Induced by: rifampin
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
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)
Probe Substrates and Inhibitors for P450s
P450
Subs trates
Preferred
Acceptable
CYP1A2
Ethoxyresorufin,
phenacet in
CYP2A6
Coumarin
CYP2B6
CYP2C8
CYP2C9
S-Mepheytoin (Ndesmethyl metabolite)
CYP2C19
CYP2D6
CYP2E1
Caffeine (low t urnover),
theophylline (low turnover),
acetanilide (most ly applied in
hepatocytes),
methoxyresorufin
Ephenyt oin (N-desmethyl
metabolite)
Paclitxel (?)
S-Warfarin,
diclofenac
Inhibitors
Preferred
Acceptable
Furafylline
a-Naphthoflavone (but
coan also activate and
inhibit CYP3A4)
8-Methoxypsoralen
Coumarin (but high
turnover), Sertraline (but
also inhibits CYP 2D6)
Bupropion (metabolite
standards?)
Glitazones (?)
Tobut amine (low turnover)
Sulphaphenazole
T iclopidine (but also
inhibits CYP2D6),
noot kat one (also inhibits
CYP2A6)
S-Mephytoin (4hydroxy met abolite),
omeprazole
Bufuralol
dextromet horphan
Metoprolol, debrisoquine,
codeine
Quinidine
Chlorzoxazone
4-Nit rophenol, lauric acid
Clomethiazole
4-Methyl pyrazole
Midazolam,
Nifedipine, felodipine,
Ketoconazole (not
test
osterone
(test
at
cyclosporin
A,
t
erfenadine,
specific, slo inhibits
Cyclosporin A
CYP3A
least 2)
erythromycin, simvast atin
CYP2C8)
Adapted from Bjornsson TD, Callaghan JT , Einolf HJ, et al. Drug Met Disp 2003; 31:815-832; See also Tucker GT, Houst on JB and
Hyang SM. Pharm Res 2001; 18: 1071-1080.
Probe Substrates and Inhibitors for P450s
Substrates
P450
Preferred
CYP1A2
Ethoxyresorufin, phenacetin
CYP2A6
Coumarin
CYP2B6
S-Mephytoin (4-hydroxy
metabolite)
Inhibitors
Acceptable
Caffeine (low turnover), theophylline
(low turnover), acetanilide (mostly
applied in hepatocytes),
methoxyresorufin
Ephenytoin (N-desmethyl metabolite)
Preferred
Acceptable
Furafylline
a-Naphthoflavone (but coan also
activate and inhibit CYP3A4)
Methoxypsoralen
Coumarin (but high turnover), Sertraline
(but also inhibits CYP2D6)
Bupropion (metabolite
standards?)
Glitazones (?)
CYP2C8
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 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 Oxidase
 Many
112
 May
interactions
listed for Selegiline!
be very significant
 Used less frequently due to safer agents
Relative Contribution to Drug Metabolism - Phase I
Evans & Relling Science 1999
Pharmacogenetics of Phase I Drug Metabolism
Weinshilboum, R. N Engl J Med 2003;348:529-537
Relative Contribution to Drug Metabolism - Phase II
Evans & Relling Science 1999
Pharmacogenetics of Phase II Drug Metabolism
Pharmacogen
etics of Phase
II Drug
Metabolism
Weinshilboum, R. N Engl J Med 2003;348:529-537
Pharmacogenetics of Acetylation
Pharma
cogene
tics of
Acetyla
tion
Weinshilboum, R. N Engl J Med 2003;348:529-537
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
Assessing the Clinical Relevance of CYP450 Drug
Interactions
1.
2.
3.
4.
5.
6.
7.
8.
Therapeutic Index and toxic potential of the
substrate
Alternate pathways of metabolism
Role of active metabolites
Consequences of metabolic inhibition of
metabolites
Are multiple P450s inhibited by inhibitor
Polymorphism of isoenzyme and patient’s
metabolizer status
Inhibitory potential of metabolites
Is inhibition helpful or harmful
Mechanisms of Interactions
Pharmacokinetic
Absorption
Distribution
Metabolism
Excretion
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
Two
secretion
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
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
Characterizing Drug Interactions
Interacting agents
Mechanism
Pharmacodynamic



Receptor inhibition
Additive effects
Pharmacokinetic


Altered absorption, distribution,
metabolism, or elimination
 Drug
- Disease
 Drug-drug
Prescription
Non-prescription
Clinical Significance

Major



Manageable



Substantial morbidity and mortality
Therapy altering
Little or no change in therapy
Optimize therapy
Intentional


Additive or synergistic effects
Enhanced pharmacokinetics
Illicit,
 Food,
recreational
supplements, herbal
products
Drug-Disease Interactions
 Liver
disease
 Renal disease
 Cardiac disease (hepatic blood flow)
 Acute myocardial infarction?
 Acute viral infection?
 Hypothyroidism or hyperthyroidism?
 SIRS ?
Drug-Food Interactions
 Tetracycline
and milk products
 Warfarin and vitamin K-containing foods
 Grapefruit juice
Effects
of grapefruit juice on felodipine pharmacokinetics and
pharmacodynamics.
Effects of grapefruit juice on felodipine pharmacokinetics and
pharmacodynamics
Dresser GK et al Clin Pharmacol Ther 2000;68(1):28–34
Drug-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, 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
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”
In Vivo Drug-Drug Interaction Studies, cont’d.
 Study
populations
Population
pharmacokinetic approach
In vitro characterization of likely targets
Subgroups
Safety concerns
 Clinical
trials
Concurrent
 Case
pharmacokinetic studies
Reports
Prediction of Drug Interactions, Resources
 Clinical
Trials
CDER
Guidance for Industry [http://0www.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: 815832.
 Case
Reports: MedWatch @ FDA
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
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.
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.
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.
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.
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.
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)
Questions?
 Blair
Holbein, Ph.D.
Presbyterian Hospital of Dallas
 Email:
bholbein@hcin.net
 Website: http://phdres.caregate.net
 Annotated bibliography
 Slides