CLINICAL PHARMACOLOGY

Rahel Birhane, MSc,

pharmacology
 What is pharmacology?
Greek words of Pharmacology
pharmakon - drug
Logos - study
 It is the study of drugs and their interactions with living
systems

The science that deals with

the fate of drugs in the body and
(pharmacokinetics)
their actions on the body
(pharmacodynamics)
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 Sub-divisions of Pharmacology
Pharmacotherapeutics:
deals with the use of drugs in the diagnosis, treatment
or prevention of a disease
 In other words, it is the clinical application of the
pharmacokinetic and pharmacodynamic knowledge of the
drug.
Clinical Pharmacology:
 study of drugs in humans (patient and volunteers)
Pharmacokinetics: study of what the body does to drugs
Pharmacodynamics : study of what drugs do to the body

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 Sub-divisions of Pharmacology
Pharmacogenetics
 deals with genetically mediated variations in drug responses.
• Chemotherapy
 deals with the use of chemotherapeutic agents to inhibit or
destroy invading microbes, parasites or cancer cells with
minimal effect on healthy living tissues.

• Toxicology
 study of poisonous or undesirable effects of drug
– Adverse effects
– Drug interactions

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 Clinical pharmacology
• It is study of drugs in humans (patient and volunteers)
• It is the apllication of pharmacokinetics and
pharmacodynamics.
• Two important goals of clinical pharmacology are
– to provide a description of conditions under which drug
actions vary among human subjects; and
– to determine mechanisms underlying this variability,
with the goal of improving therapy with available drugs
as well as pointing to new drug mechanisms that may
be effective in the treatment of human disease.
 Pharmacokinetics
• Pharmacokinetics is the study of how a drug
reaches its target in the body and how it is
affected on that journey, i.e; effect of the
body on the drug.
• Pharmacokinetics is the study of how is the
drug absorbed, distributed, metabolized and
excreted in the body
 PHARMACOKINETICS con’d
 Application

• It provides a rational basis for doses of a drug

• It also helps in dosage adjustment in altered

physiological and pathological states like aging,
renal or hepatic impairment.

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 What is clinical
pharmacokinetics ?
• Study of the time course of a drug’s
movement through the body.
• Clinical pharmacokinetics relies on a
relationship between the pharmacological
effects of a drug and a measurable
concentration of the drug (e.g., in blood or
plasma).
• provides a framework within which drug
dose adjustments can be made.

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 CLINICAL PHARMACOKINETICS
• The four most important parameters
governing drug disposition are
– clearance, a measure of the body’s efficiency in
eliminating drug;
– volume of distribution, a measure of the apparent
space in the body available to contain the drug;
– elimination t1/2, a measure of the rate of removal
of drug from the body; and
– bioavailability, the fraction of drug absorbed as
such into the systemic circulation.

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 CLINICAL PHARMACOKINETICS
• This approach allows prediction of how factors
such as disease, concomitant drug therapy, or
genetic variants affect these parameters, and
how dosages therefore should be adjusted.
• In this way, the chances of under treatment
due to low drug concentrations or adverse
effects due to high drug concentrations can be
minimized.

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 Bioavailability
Bioavailability refers to the rate and extent of
absorption of a drug from dosage form in the
unchanged form.
 Bioavailability （ F ）： is defined as the fraction of
the administered drug reaching the systemic
circulation as intact drug.

BA = Quantity of drug reaching systemic circulation

Quantity of drug administered

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 Bioavailability
– IV = 100%
– Oral < 100%
– Other routes ≤ 100%

– Example: Cyclosporine
• Bioavailability IV = 100%
• Bioavailability Oral = 25%

• Therefore, oral dose 4 x IV dose

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 Major Factors Affecting Drug Bioavailability

• First-Pass Metabolism (liver

and intestine)
• Efflux from enterocytes (active
drug transporters)
• Physiochemical properties of
drug that affect absorption
(polarity, size, etc)
• Nature of drug formulation
(binders, solubilizers, etc)
IV administration circumvents
these factors

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14
Absolute bioavailability (Fabs) : compares the
amount in the systemic circulation after
intravenous (reference) and extravascular
(usually oral) dosing
Fabs = AUCpo/AUCiv for the same dose
• between 0 and 100% (occasionally >100%)

Relative bioavailability (Frel)

• compares one drug product (e.g. tablet) relative
to another drug product (solution)

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ailability = AUC (po) X 100
AUC (iv)
= 50 mcg/ml/min X 100
cg/ml/min

= 50%
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 Clinical Implications of Altered
Bioavailability
• Some drugs undergo near complete presystemic
metabolism and thus cannot be administered orally.
E.g. Lidocaine, nitroglycerin
• Other drugs undergo very extensive presystemic
metabolism but can still be administered by the oral
route, using much higher doses than those required
intravenously.
• E.g. a typical IV dose of verapamil would be 1 to 5
mg, compared to the usual single oral dose of 40 to
120 mg.
• The rate of absorption can be an important consideration for
determining a dosage regimen,
– for drugs with a narrow therapeutic ratio.
• If absorption is too rapid, then the resulting high concentration
may cause adverse effects not observed with a more slowly
absorbed formulation.
• slow absorption is deliberately designed into “slow-release” or
“sustained-release” drug formulations in order to minimize
variation in plasma concentrations during the interval between
doses,
– because the drug’s rate of elimination is offset by an equivalent
rate of absorption controlled by formulation factors .
 Distribution

• Process by which a drug reversibly leaves the site of

administration and distributed throughout the
tissues of the body
• A prerequisite for most drugs to reach target organs
in therapeutic concentrations
•Factors affecting drug distribution ：
Blood flow
Initially, liver, kidney, brain, and other well-
perfused organs receive most of the drug,
whereas delivery to muscle, most viscera, skin, and
fat is slower.
This second distribution phase may require minutes
to several hours before the concentration of drug in
tissue is in equilibrium with that in blood.
Physical barriers
Blood-brain and placenta barriers (bound/
ionized drug can not pass through the BBB)

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•Factors affecting drug distribution ：
Binding of drugs to proteins
 Most drugs found in the vascular
compartment are bound reversibly with one or
more of the macromolecules in plasma.
 Many acidic drugs bind principally to albumin
， while basic drugs frequently bind to other
plasma proteins such as lipoproteins and α1-
acid glycoprotein (α1-AGP)
 Only the unbound drugs can diffuse through the
capillary wall, produce its systemic effects, be
metabolized and be excreted.

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 DISTRIBUTION
• Protein binding
– Having saturation and competitive inhibition.
– Patient with low plasma protein (uraemia, hepatic
disease) or old people with low albumin in plasma ,their
percentage of protein binding may be changed, amount
of unbound drug increases, effect precipitate.
– protein binding acts as a temporary store of a drug and
tends to prevent large fluctuations in concentration of
unbound drug in the body fluids
– It delays its metabolic degradation--- prolong its action

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 DISTRIBUTION
Affinity of drugs to certain organs:
• Many drugs accumulate in tissues at higher concentrations than
those in the extracellular fluids and blood.
• Tissue binding of drugs usually occurs with cellular constituents
such as proteins, phospholipids, or nuclear proteins and
generally is reversible.
• A large fraction of drug in the body may be bound in this fashion
and serve as a reservoir that prolongs drug action
• Such tissue binding and accumulation also can produce local
toxicity.
• E.g . fat may serve as a reservoir for lipid-soluble drugs.

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 Clinical Implications of Altered
Protein Binding
• For drugs that are normally highly bound to plasma proteins
(90%), small changes in the extent of binding (e.g., due to
disease) produce a large change in the amount of unbound
drug, and hence drug effect.
• The acute-phase reactant 1- acid glycoprotein binds to basic
drugs, such as lidocaine or quinidine, and is increased in a
range of common conditions, including myocardial infarction,
surgery, neoplastic disease, rheumatoid arthritis, and burns.
– This increased binding can lead to reduced pharmacologic effects at
therapeutic concentrations of total drug.
•
 Clinical Implications of Altered
Protein Binding
• Conditions such as hypoalbuminemia, liver disease,
and renal disease can decrease the extent of drug
binding, particularly of acidic and neutral drugs, such
as phenytoin.
– Here, plasma concentration of free drug is
increased, so drug efficacy and toxicity are
enhanced if total (free bound) drug is used to
monitor therapy.
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 DISTRIBUTION
Relevance?
• Explains differences in onset of activity
e.g., fentanyl vs. morphine
• Explains the prolonged duration of midazolam
after long-term use (accumulation)
• Helps predict medication removal by renal
replacement therapy
• drug distribution into the brain may be modulated
by changes in P-glycoprotein function.

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 Drug Metabolism
 The process by which drugs are inactivated and
transformed into a form that can be eliminated from
the body
 The chemical modification of drugs with the overall
goal of getting rid of the drug
 Usually in liver
Metabolism Excretion
More polar
Drug
(water soluble)
Drug

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 Consequences of Drug Metabolism

Substrate Enzyme
(drug) Metabolite

Active Inactive

Detoxification
Toxic Nontoxic

Inactive Active Prodrug

Activation
Nontoxic Toxic Reactive metabolite

e.g. Isoniazid → Acetylisoniazid (mutagenicity,

teratogenicity, carcinogenicity, hepatotoxicity)
 Phases of Drug Metabolism
Phase I

“Functionalization” reactions
Involve introduction or unmasking of a polar
functional group (e.g., -OH, -NH2, -SH, -COOH) on
substrate to ↑ hydrophilicity and prepare for Phase II
metabolism
Reaction classes:
• oxidation, reduction, hydrolysis

Oxidative metabolism mediated by cytochrome P450

(CYP) most important Phase I pathway!
 Phases of Drug Metabolism
Phase II

“Conjugation” reactions

Involve addition of an endogenous compound (e.g.,

glucuronic acid, amino acid, acetyl group, sulfate) to
functional group contained on drug molecule or
product of Phase I metabolism
↑ hydrophilicity, detoxification, excretion
Reaction classes:
• glucuronidation, sulfation, glutathione
conjugation, acetylation, methylation
 Cytochrome P450

Most significant contributors to drug metabolism

Catalyze biotransformation of endogenous
substrates, dietary compounds, environmental
chemicals, and up to 60% to 80% of drugs currently
marketed!
Present in species from bacteria to mammals;
localized intracellularly in smooth endoplasmic
reticulum
> 270 gene families described; > 18 families in man

CYP1, CYP2, and CYP3 families most clinically relevant

 Contribution of CYP
to Drug Metabolism

1A2
3%
2C
18%

2A6
1%

3A
52%

2D6
25%

2E
1%

Adapted from Clin Pharmacokinet 1997;32:210.

CYP450 Mephenytoin Midazolam Chlorzoxazone Retinoids
Substrates Omeprazole CyA/Tacrolimus Acetaminophen Paclitaxel
Diazepam Losartan CCBs Nitrosamines
Nicotine Statins Caffeine Anesthetics SSRIs
NSAIDs
Buproprion Cisapride Theophyline Desipramine
Warfarin
Coumarin Tolbutamide Terfenadine Imipramine Nortriptyline
Phenytoin ß-blockers
Debrisoquine
D-methorphan

2B6 2A6 2C19 2C9 3A4/5 1A2 2E1 2D6 2C8

< 1% 4% 2% 18% 30% 13% 7% 4% < 1%

Inhibitors Azoles Azoles Azoles Azoles Disulfiram

Macrolides Macrolides Quinidine
Cimetidine Cimetidine Methadone
Grapefruit Grapefruit Cimetidine

Barbs Barbs Barbs Ethanol Rifampin

Omeprazole
Inducers Rifampin Rifampin Rifampin Barbs
Isoniazid
Dexamethasone Benzene
Rifampin
Carbamazepine PAHs
St. John’s Wort
 Drug Metabolism

Changes in drug metabolism are more commonly

the result of acquired alteration of hepatocyte
function via drug interactions than from intrinsic
hepatic derangements.

May be genetically determined:

• Racial differences in functionality of many Phase I
reactions (CYP 2D6, 2C9, 2C19, etc) N Engl J Med.
2003;348:529.
 Inhibitors and inducers of microsomal
enzymes

CYP450 can be induced or inhibited by drugs

•Inhibitors: cimetidine prolongs action of drugs or
inhibits action of those biotransformed to active
agents (pro-drugs)

•Inducers: barbiturates, carbamazepine shorten

action of drugs or increase effects of those
biotransformed to active agents

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Drug Metabolism Often Results in Active Metabolites
that Can Accumulate (Especially in Renal Disease)

Normeperidine from meperidine

• Epileptogenic
Morphine 3- and 6-glucuronide salts
• Prolonged narcosis
Desacetylvecuronium from vecuronium
• Prolonged paralysis
Cyanide from nitroprusside
• Death
Hydroxymidazolam from midazolam
• 66% the activity of the parent drug
 Drug Excretion

Largely the domain of the kidney

• Minor pathways: bile, lung, and feces
• The rate of excretion influences the duration of action of drug.
• The drug that is excreted slowly, the concentration of drug in
the body is maintained and the effects of the drug will
continue for longer period.
 Half-Life ， t1/2
• The time it takes for half of drug to be eliminated from the body.

Give 100 mg of a drug

1 half-life ………….. 50
2 half-lives………… 25
3 half-lives …….…..12.5
4 half-lives ………… 6.25
5 half-lives ………… 3.125
6 half-lives …………. 1.56
5 half-lives = 97% of drug eliminated

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two-kinds of elimination kinetics
• First-order elimination kinetics (t1/2 = 0.693/k)
• Constant fraction of total drug stores eliminated in a given
time

– fixed half time.

Almost all drugs follow linear kinetics (except in overdose
situations)

• Dose increases result in proportional increases in serum

levels
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 • Zero order kinetics (t1/2 = 0.5 Co/k)
The eliminated rate has no relationship with the
drug concentration.
Constant amount (vs. %) eliminated per unit time
Having no fixed half life.
• Examples - phenytoin, aspirin, ethanol

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 Steady-State
• Steady-state occurs after a drug has been given
for approximately five elimination half-lives.
• At steady-state the rate of drug administration
equals the rate of elimination

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The time to reach steady
state is 4~6 t1/2’s

Concentration due to
repeated doses

Concentration due to a single dose

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 T1/2
Determines the frequency of dosing required to
maintain therapeutic plasma levels of a drug
– Determines the time required to reach steady
state and the dosage interval.
• Half-life is determined by clearance (CL) and
volume of distribution (VD) and the
relationship is described by the following
equation:
t1/2= 0.693 Vd/Cl
 Clearance
• Ability of organs of elimination (e.g. kidney,
liver) to “clear” drug from the bloodstream
• Volume of fluid which is completely cleared
of drug per unit time
• Units are in L/hr or L/hr/kg
• The rate of elimination of a drug from the body
relative to the concentration of the drug in
plasma (mainly occurs in the kidney).
• Cl=Elimination rate/Plasma drug conc

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 Clearance
• While elimination half-life determines the
time required to achieve steadystate plasma
concentrations (Css), the magnitude of that
steady state is determined by clearance (Cl)
and dose alone.
• For a drug administered as an intravenous
infusion, this relationship is
• Css= dosing rate/Cl or dosing rate = Cl * Css

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 Clearance
• Genetic variants, drug interactions, or
diseases that reduce the activity of drug-
metabolizing enzymes or excretory
mechanisms may lead to decreased clearance
and hence a requirement for downward dose
adjustment to avoid toxicity.

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 Loading dose
• It is a first dosing amount that achieves Css rapidly, before
given routine dose
• Loading dose=Amount in the body achieving Css immediately
following the loading dose

• Loading dose is a beginning dose that promptly raises the

concentration of drug in plasma to the target concentration
• Loading dose=Two times the amount of routine
administration dose
=Administrated dosage·2

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 Loading Dose

Dose = Cp(Target) x VD

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 Question
• What Is the is the loading dose required
for drug A if;
• Target concentration is 10 mg/L
• VD is 0.75 L/kg
• Patients weight is 75 kg

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 Maintenance Dose

• Maintenance Dose = CL x CpSSav

• CpSSav is the target average steady state drug

concentration

• The units of CL are in L/hr or L/hr/kg

• Maintenance dose will be in mg/hr so for total daily

dose will need multiplying by 24
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 Question
• What maintenance dose is required for
drug A if;
• Target average SS concentration is 10
mg/L
• CL of drug A is 0.015 L/kg/hr
• Patient weighs 75 kg

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 HIGH-RISK PHARMACOKINETICS
• Many drugs undergo elimination by multiple drug-
metabolizing or excretory pathways.
– absence of one pathway (due to a genetic variant,
disease related or drug interaction) may not have a large
impact on drug concentrations or drug actions.
• However, other drugs utilize a single pathway exclusively for
drug elimination.
– In such cases, any condition that inhibits that pathway
(be it disease-related, genetic, or due to a drug
interaction)can lead to dramatic changes in drug
concentrations and hence effect.
 HIGH-RISK PHARMACOKINETICS
Examples
• digoxin toxicity when P-glycoprotein, the major route of digoxin
elimination, is inhibited
• potentially fatal bone marrow aplasia due to azathioprine or 6-
mercaptopurine in patients with genetically determined absence
of function of thiopurine S-methyltransferase (TPMT).
• the antiarrhythmic flecainide is eliminated by both renal
excretion and CYP2D6-mediated metabolism.
– Rare patients with both renal dysfunction and absent CYP2D6
activity (on a genetic basis or because of drug interactions) may
develop severe adverse reactions related to high plasma
concentrations.
 PRINCIPLES OF
PHARMACODYNAMICS
• Once a drug accesses a molecular site of action, it alters the
function of that molecular target, with the ultimate result of a
drug effect.
• For drugs used in the urgent treatment of acute symptoms,
little or no delay is anticipated (or desired)between the drug-
target interaction and the development of a clinical effect.
– Examples include vascular thrombosis, shock, malignant
hypertension, status epilepticus, or arrhythmias.
• For many conditions, however, the indication for therapy is less
urgent, and in fact a delay between the interaction of a drug
with its pharmacologic target( s) and a clinical effect is common.
 PRINCIPLES OF
PHARMACODYNAMICS
• Pharmacokinetic mechanisms that can contribute to such a delay
include uptake into peripheral compartments or generation and
accumulation of active metabolites.
• A common pharmacodynamic mechanism is that the clinical effect
develops as a downstream consequence of the initial molecular
effect the drug produces.
• EXAMPLES
– administration of a proton-pump inhibitor or anH2-receptor
blocker produces an immediate increase in gastric pH but ulcer
healing that is delayed.
– Cancer chemotherapy inevitably produces delayed therapeutic
effects, often long after drug is undetectable in plasma and tissue.
 PRINCIPLES OF
PHARMACODYNAMICS
• A therapeutic drug effect assumes the presence of
underlying pathophysiology.
– a drug may produce no action, or a different spectrum of
actions, in unaffected individuals compared to patients.
• Further, concomitant disease can complicate interpretation
of response to drug therapy, especially adverse effects.
• For example, high doses of anticonvulsants such as
phenytoin may cause neurologic symptoms, which may be
confused with the underlying neurologic disease.
 PRINCIPLES OF
• PHARMACODYNAMICS
The concept that a drug interacts with a specific molecular
receptor does not imply that the drug effect will be constant
over time, even if stable drug and metabolite concentrations
are maintained.
• The drug receptor interaction occurs in a complex biologic
milieu that itself can vary to modulate the drug effect.
• ion channel blockade by drugs, an important anticonvulsant
and antiarrhythmic effect, is often modulated by membrane
potential, itself a function of factors such as extracellular
potassium or ischemia. ---Thus, the effects of these drugs
may vary depending on the external milieu.
 PRINCIPLES OF
PHARMACODYNAMICS
• Receptors may be up- or down regulated by disease
or by the drug itself.
• βadrenergic blockers upregulate β receptor density
during chronic therapy.
– While this effect does not usually result in
resistance to the therapeutic effect of the drugs, it
may produce severe βagonist–mediated effects
(such as hypertension or tachycardia) if the
blocking drug is abruptly withdrawn.
PHARMACOGENETICS
 Same symptoms,
Different patients
Same findings,
Same disease? Same drug
Same dose

Why does drug response vary?

Genetic Different Effects

Differences
Ethnicity Possible Reasons:
SNP Age
G Individual variation
Pregnancy By chance…
Genetic factors
A Disease
Drug interactions
……
 Why does drug response vary?
•Genetic variation
•Primarily two types of genetic mutation events create all
forms of variations:
Single base mutation which substitutes one nucleotide for
another
--Single nucleotide polymorphisms (SNPs)
Insertion or deletion of one or more nucleotide(s)
• --Tandem Repeat Polymorphisms
• --Insertion/Deletion Polymorphisms
•Polymorphism: A genetic variation that is observed at a
frequency of >1% in a population
 How can genetic variations
identified?
• Clinically important genetic variants are
identified either by
• directly establishing DNA sequence
(genotyping) or
• by phenotyping: exposing a large group of
otherwise healthy subjects to a specific probe
substrate for the metabolizing enzyme under
study and observing the distribution of activity
 Due to individual variation…
20-40% of patients benefit from an approved drug
70-80% of drug candidates fail in clinical trials
Many approved drugs removed from the market due to
adverse drug effects

•The use of DNA sequence information to measure and

predict the reaction of individuals to drugs.
Personalized drugs
Faster clinical trials Pharmacogenetics
Less drug side effects
 Pharmacogenetics
•“Study of interindividual variation in DNA sequence related to
drug absorption and disposition (Pharmacokinetics) and/or drug
action (Pharmacodynamics) including polymorphic variation in
genes that encode the functions of transporters, metabolizing
enzymes, receptors and other proteins.”
•“The study of how people respond differently to medicines due
to their genetic inheritance is called pharmacogenetics.”
•“Correlating heritable genetic variation to drug response”
•An ultimate goal of pharmacogenetics is to understand how
someone's genetic make-up determines, how well a medicine
works in his or her body, as well as what side effects are likely to
occur.
• “Right medicine for the right patient”
 Pharmacogenetics VS. Pharmacogenomics

•Pharmacogenetics: Study of variability in drug

response determined by single genes.

•Pharmacogenomics: Study of variability in drug

response determined by multiple genes within
the genome.
Pharmacogene The study of variations in genes
tics that determine an individual’s
response to drug therapy.

Genetic Common variation in DNA

Polymorphism: sequence (i.e. in >1% of
SNPs; INDEL; population)
VNTRs

Potential Target Genes are those that

encode:
Drug-metabolizing enzymes
Transporters
Drug targets
 Clinical Consequences of Genetic
Polymorphisms
Toxicity
• Can be profound for drugs with a narrow therapeutic index that are
inactivated
- mercaptopurine, fluorouracil

Reduced efficacy or therapeutic failure

• Drugs that are activated
- codeine
 Determinants of Drug Efficacy and Toxicity

A patient’s response to a drug may depend on factors that can

vary according to the alleles that an individual carries, including :
dose administered Pharmacokinetic factors
Pharmacokinetics
- Absorption
ABSORPTION
- Distribution
concentration in DISTRIBUTION drug in tissues - Metabolism
systemic circulation of distribution
ELIMINATION - Elimination

metabolism and/or excretion

concentration at Pharmacodynamic factors
site of action
- Target proteins
Pharmacologic effect - Downstream messengers

Clinical response
Pharmacodynamics
Toxicity Efficacy
 Pharmacogenetics

N Engl J Med. 2003;348:529.

 Examples:

•EM phenotype: Extensive metabolizer; IM phenotype: intermediate metabolizer; PM

phenotype: poor metabolizer; UM phenotype: ultrarapid metabolizers
 Codeine and
Cytochrome P450 CYP2D6
• Codeine is a commonly used opioid
– Codeine is a prodrug
– It must be metabolized into morphine for
activity
• Cytochrome P450 allele CYP2D6 is the
metabolizing enzyme in the liver
• 7% of Caucasians are missing one copy of
the Cytochrome P450 CYP2D6 gene
– codeine does not work effectively in these
individuals

Courtesy of Michelle Whirl-Carillo

 Atypical Plasma Cholinesterase
SUCCINYLCHOLINE
O O
+ +
(H3C)3NH2CH2C O C CH2CH2 C O CH2CH2N(CH3)3

choline succinylmonocholine

Hydrolysis by pseudocholinesterase

•a rapid acting, rapid recovery muscle relaxant

•usual paralysis lasted 2 to 6 min in patients
•occasional pt exhibited paralysis lasting hrs
•cause identified as an “atypical” plasma cholinesterase
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N-ACETYLTRANSFERASE ACTIVITY

ETHNIC DIFFERENCES IN THE DISTRIBUTION OF

ACETYLATOR PHENOTYPE

Population % Slow % Hetero Fast % Homo Fast

South Indians 59 35.6 5.4
Caucasians 58.6 35.9 5.5
Blacks 54.6 38.6 6.8
Eskimos 10.5 43.8 45.7
Japanese 12 45.3 42.7
Chinese 22 49.8 28.2

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 XENOBIOTICS SUBJECT TO POLYMORPHIC ACETYLATION IN MAN

Carcinogenic
Hydrazines Arylamines Arylamines
isoniazid dapsone benzidine
hydralazine procainamide -naphthylamine
phenylzine sulfamethazine 4-aminobiphenyl
acetylhydrazine sulfapyridine
hydrazine aminoglutethimide

Drugs metabolized to amines

sulfasalazine nitrazepam
clonazepam caffeine

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 ADVERSE EFFECTS TO SULFASALAZINE IN
PATIENTS WITH INFLAMMATORY BOWEL
DISEASE
Frequency of side effect
Side Effect Slow Acetylators Fast Acetylators
cyanosis 9 1
hemolysis 5 0
transient reticulocytosis 6 0

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FDA Requires Genetic Tests
for Certain Therapies

Courtesy of Michelle Whirl-Carillo

 Variability in the molecular targets with
which drugs interact
• polymorphisms that alter the expression or function of drug targets
modulate their actions in patients—are also being recognized.
 example, genome-wide searches in families with premature
Alzheimer’s disease have associated variants in the APOE locus with
the disease
• The E4 allele of the gene has been associated with a worse prognosis, a
finding that has been attributed to reduced expression of choline
acetyltransferase.
• Further, this polymorphism is also linked to response to the
acetylcholinesterase inhibitor tacrine; a beneficial response appears to
be more common in patients with the prognostically more benign
APOE2 or APOE3 alleles (the target molecule is expressed more
abundantly).
 Variability in the molecular targets with
which drugs interact
• Polymorphisms in the β2-receptor gene have also been
associated with response to inhaled β2-receptor agonists,
• response to the 5-lipoxygenase inhibitor zileuton in
asthma has been linked to polymorphisms that determine
the expression level of the 5-lipoxygenase gene.
• Herceptin, which potentiates anthracycline- related
cardiotoxicity, is ineffective in breast cancers that do not
express the herceptin receptor; thus, genotyping” the
tumor is a mechanism to avoid potentially toxic therapy in
patients who would derive no benefit.