PHARMACOKINETICS

AND
PHARMACOGENOMICS
DR. CHRISTINE MAY R. VALDEZ
PHARMACOKINETIC PRINCIPLES
• To produce useful therapeutic effects most drugs must be
absorbed, distributed, and eliminated
• Movement of Drugs in the Body
• To reach its receptors and bring about a biologic effect a drug
molecule (benzodiazepine sedative) must travel from the site of
administration (gastrointestinal tract) to the site of action (brain)
• Absorption: absorption from the site of administration permits entry
of the drug (either directly or indirectly) into plasma
• Distribution: the drug may then reversibly leave the bloodstream and
distribute into the interstitial and intracellular fluids.
• Metabolism: the drug may be biotransformed by metabolism by the
liver or other tissues
• •Elimination: the drug and its metabolites are eliminated from the
body in urine, bile, or feces
A. Routes of Administration
• Drugs usually enter the body at sites remote from the target tissue or
organ  require transport by the circulation to the intended site of
action
• To enter the bloodstream drug must be absorbed from its site of
administration
• Rate and efficiency of absorption differ depending on a drug’s route of
administration
• amount absorbed into the systemic circulation divided by the amount
of drug administered constitutes its bioavailability by that route
Enteral administration
• (administering a drug by mouth) is the safest and most common,
convenient, and economical method of drug administration
• drug may be swallowed, allowing oral delivery, or it may be placed
under the tongue (sublingual), or between the gums and cheek
(buccal), facilitating direct absorption into the bloodstream
1. Oral:
• Oral drugs are easily self-administered, and toxicities and/or overdose
of oral drugs may be overcome with antidotes, such as activated
charcoal
• pathways involved in oral drug absorption are the most complicated,
and the low gastric pH inactivates some drugs
• wide range of oral preparations is available including enteric-coated
and extended-release preparations
a. Enteric-coated preparations:
• An enteric coating is a chemical envelope that protects the drug from
stomach acid, delivering it instead to the less acidic intestine, where
the coating dissolves and releases the drug
• Enteric coating is useful for certain drugs (omeprazole) that are acid
unstable
• Drugs that are irritating to the stomach, such as aspirin, can be
formulated with an enteric coating that only dissolves in the small
intestine protecting the stomach
b. Extended-release preparations:
• Extended-release (abbreviated ER or XR) medications have special
coatings or ingredients that control the drug release allowing for
slower absorption and a prolonged duration of action
• may maintain concentrations within the therapeutic range over a
longer period of time, as opposed to immediate-release dosage
forms result in larger peaks and troughs in plasma concentration
• are advantageous for drugs with short half-lives
• Eg: half-life of oral morphine is 2 to 4 hours, and it must be
administered six times daily to provide continuous pain relief
2. Sublingual/buccal:
• Placement under the tongue allows a drug to diffuse into the capillary
network and enter the systemic circulation directly
• Sublingual administration has advantages ease of administration,
rapid absorption, bypass of the harsh gastrointestinal (GI)
environment, and avoidance of first pass metabolism
• buccal route (between the cheek and gum) is similar to the sublingual
route
B. Parenteral routes
• introduces drugs directly into the systemic circulation
• used for drugs that are poorly absorbed from the GI tract (heparin) or
unstable in the GI tract (insulin)
• also used if a patient is unable to take oral medications (unconscious
patients) and in circumstances that require a rapid onset of action
• have the highest bioavailability and are not subject to first-pass
metabolism or the harsh GI environment
• provides the most control over the actual dose of drug delivered to
the body
• are irreversible and may cause pain, fear, local tissue damage, and
infections
1. Intravenous (IV):
• most common parenteral route
• useful for drugs that are not absorbed orally, such as the
neuromuscular blocker rocuronium
• permits a rapid effect and a maximum degree of control over the
amount of drug delivered
• When injected as a bolus full amount of drug is delivered to the
systemic circulation almost immediately
• as an IV infusion drug is infused over a longer period of time
resulting in lower peak plasma concentrations and an increased
duration of circulating drug levels
• may inadvertently introduce infections through contamination at the
site of injection
• also precipitate blood constituents, induce hemolysis, or cause other
adverse reactions if the medication is delivered too rapidly and high
concentrations are reached too quickly
• patients must be carefully monitored for drug reactions, and the rate
of infusion must be carefully controlled
2. Intramuscular (IM):
• can be in aqueous solutions, which are absorbed rapidly, or in
specialized depot preparations, which are absorbed slowly
• Depot preparations often consist of a suspension of the drug in a
nonaqueous vehicle such as polyethylene glycol
• As the vehicle diffuses out of the muscle drug precipitates at the
site of injection dissolves slowly providing a sustained dose over
an extended period of time
3. Subcutaneous (SC):
• provides absorption via simple diffusion and is slower than the IV
route
• minimizes the risks of hemolysis or thrombosis associated with IV
injection and may provide constant, slow, and sustained effects
• should not be used with drugs that cause tissue irritation severe
pain and necrosis may occur
• Eg: insulin and heparin
2. Nasal inhalation:
• involves administration of drugs directly into the nose
• Eg: nasal decongestants, such as oxymetazoline, and corticosteroids,
such as mometasone furoate
• Desmopressin is administered intranasally in the treatment of
diabetes insipidus
4. Topical:
• used when a local effect of the drug is desired
• Eg: clotrimazole is a cream applied directly to the skin for the
treatment of fungal infections
5. Transdermal:
• achieves systemic effects by application of drugs to the skin, usually
via a transdermal patch
• rate of absorption can vary markedly, depending on the physical
characteristics of the skin at the site of application, as well as the lipid
solubility of the drug
• most often used for the sustained delivery of drugs, such as the
antianginal drug nitroglycerin, the antiemetic scopolamine, and
nicotine transdermal patches, which are used to facilitate smoking
cessation
6. Rectal:
• Because 50% of the drainage of the rectal region bypasses the portal
circulation, the biotransformation of drugs by the liver is minimized
with rectal administration
• has the additional advantage of preventing destruction of the drug in
the GI environment
• also useful if the drug induces vomiting when given orally, if the
patient is already vomiting, or if the patient is unconscious
ABSORPTION OF DRUGS
Absorption
• transfer of a drug from the site of administration to the
bloodstream
• rate and extent of absorption depend on the environment
where the drug is absorbed, chemical characteristics of the
drug, and the route of administration (which influences
bioavailability)
• Routes of administration other than intravenous may result
in partial absorption and lower bioavailability
A. Permeation
movement of drug molecules into and within the biologic environment
1. Aqueous diffusion
• movement of molecules through the watery extracellular and intracellular
spaces
• membranes of most capillaries have small water-filled pores that permit
the aqueous diffusion of molecules up to the size of small proteins
between the blood and the extravascular space
• a passive process governed by Fick’s law
• capillaries in the brain, testes, and some other organs lack aqueous pores,
and these tissues are less exposed to some drugs
2. Lipid diffusion
• passive movement of molecules through membranes and other lipid
barriers
• governed by Fick’s law
1. Passive diffusion:
• driving force for passive absorption of a drug is the concentration
gradient across a membrane separating two body compartments
• drug moves from a region of high concentration to one of lower
concentration
• does not involve a carrier, is not saturable, and shows a low structural
specificity
• majority of drugs are absorbed by this mechanism
• Water-soluble drugs penetrate the cell membrane through aqueous
channels or pores
• lipid-soluble drugs readily move across most biologic membranes due
to their solubility in the membrane lipid bilayers
2. Facilitated diffusion:
• Other agents can enter the cell through specialized transmembrane
carrier proteins that facilitate the passage of large molecules
• These carrier proteins undergo conformational changes allowing
the passage of drugs or endogenous molecules into the interior of
cells and moving them from an area of high concentration to an area
of low concentration
• does not require energy, can be saturated, and may be inhibited by
compounds that compete for the carrier
3. Transport by special carriers
• Drugs that do not readily diffuse through membranes may be
transported across barriers by mechanisms that carry similar
endogenous substances
• very large number of such transporter molecules have been identified
• not governed by Fick’s law
• Capacity limited
Active transport:
• involves specific carrier proteins that span the membrane
• drugs that closely resemble the structure of naturally occurring
metabolites are actively transported across cell membranes using
specific carrier proteins
• Energy-dependent active transport is driven by the hydrolysis of
adenosine triphosphate
• capable of moving drugs against a concentration gradient, from a
region of low drug concentration to one of higher drug concentration
• are selective and may be competitively inhibited by other
cotransported substances
• Examples are transporters for ions (Na+ / K+ ATPase), for
neurotransmitters (transporters for serotonin, norepinephrine), for
metabolites (glucose, amino acids), and for foreign molecules
(xenobiotics) such as anticancer drugs
• After release amine neurotransmitters (dopamine, norepinephrine,
and serotonin) and some other transmitters are recycled into nerve
endings by transport molecules
4. Endocytosis
• occurs through binding of the transported molecule to specialized
components (receptors) on cell membranes, with subsequent
internalization by infolding
• contents of the resulting intracellular vesicle are released into the
cytoplasm of the cell
• permits very large or very lipid-insoluble chemicals to enter cells
• large molecules such as proteins may cross cell membranes by
endocytosis
• Smaller, polar substances such as vitamin B12 and iron combine with
special proteins (B12 with intrinsic factor and iron with transferrin),
and the complexes enter cells by this mechanism
• Because the substance to be transported must combine with a
membrane receptor endocytotic transport can be quite selective
Exocytosis
• the reverse process
• expulsion of material that is membrane-encapsulated inside the cell
from the cell
• Most neurotransmitters are released by exocytosis
B. Fick’s Law of Diffusion
• Fick’s law predicts the rate of movement of molecules across a
barrier
• concentration gradient (C1 − C2) and permeability coefficient for the
drug and the area and thickness of the barrier membrane are used to
compute the rate as follows:
• drug absorption is faster from organs with large surface areas, such as
the small intestine, than from organs with smaller absorbing areas
• Drug absorption is faster from organs with thin membrane barriers
(lung) than from those with thick barriers (skin)
C. Water and Lipid Solubility of Drugs
1. Solubility
• aqueous solubility of a drug is often a function of the electrostatic
charge (degree of ionization, polarity) of the molecule water
molecules behave as dipoles and are attracted to charged drug
molecules forming an aqueous shell around them
• lipid solubility of a molecule is inversely proportional to its charge
• Many drugs are weak bases or weak acids
• pH of the medium determines the fraction of molecules charged
(ionized) versus uncharged (nonionized)
If the pKa of the drug and the pH of the medium are known fraction of molecules in
the ionized state can be predicted by means of the Henderson-Hasselbalch equation:
2. Ionization of weak acids and
bases
• Weak bases are ionized more
polar and more water-soluble
when they are protonated
• Weak acids are not ionized
less water-soluble when they are
protonated
• Henderson-Hasselbalch relationship is important when it is
necessary to estimate or alter the partition of drugs between
compartments of differing pH
• most drugs are freely filtered at the glomerulus
• lipid-soluble drugs can be rapidly reabsorbed from the tubular urine
• Excretion of weak acid drug (aspirin)  faster in alkaline urine
drug that is a weak acid dissociates to its charged polar form in
alkaline solution cannot readily diffuse from the renal tubule back
into the blood drug is trapped in the tubule
• Excretion of a weak base (pyrimethamine, amphetamine)  faster in
acidic urine
B. Blood Flow
• influences absorption from intramuscular and subcutaneous sites and
gastrointestinal tract
• High blood flow maintains a high drug depot-to-blood concentration
gradient  facilitates absorption
C. Concentration
• important in determining the concentration gradient relative to the
blood
• Concentration gradient is a major determinant of the rate of
absorption
• Drug concentration in the vehicle is particularly important in the
absorption of drugs applied topically
Total surface area available for absorption:
• With a surface rich in brush borders containing microvilli intestine
has a surface area about 1000-fold that of the stomach absorption
of the drug across the intestine more efficient
4. Contact time at the absorption surface:
• If a drug moves through the GI tract very quickly ( severe diarrhea) it
is not well absorbed
• Anything that delays the transport of the drug from the stomach to
the intestine delays the rate of absorption of the drug
Distribution of Drugs
A. Determinants of Distribution
1. Size of the organ
• determines the concentration gradient between blood and the organ
E.g. skeletal muscle is a very large organ can take up a large amount
of drug because the concentration in the muscle tissue remains low
(blood tissue gradient high) even after relatively large amounts of drug
have been transferred
• In contrast:
brain is smaller distribution of a smaller amount of drug into it will
raise the tissue concentration and reduce to zero the blood-tissue
concentration gradient preventing further uptake of drug unless it is
actively transported
2. Blood flow
• Blood flow to the tissue is an important determinant of the rate of
uptake of drug
• blood flow may not affect the amount of drug in the tissue at
equilibrium
• well-perfused tissues (brain, heart, kidneys, and splanchnic organs)
usually achieve high tissue concentrations sooner than poorly
perfused tissues (fat, bone)
3. Solubility
• Solubility of a drug in tissue influences the concentration of the drug
in the extracellular fluid surrounding the blood vessels
• If drug is very soluble in the cells concentration in the perivascular
extracellular space will be lower and diffusion from the vessel into the
extravascular tissue space will be facilitated
some organs (brain) have a high lipid content and thus dissolve a high
concentration of lipid-soluble agents rapidly
4. Binding
• Binding of a drug to macromolecules in the blood or a tissue
compartment tends to increase the drug’s concentration in that
compartment
warfarin is strongly bound to plasma albumin restricts warfarin’s
diffusion out of the vascular compartment
chloroquine is strongly bound to extravascular tissue proteins
marked reduction in the plasma concentration of chloroquine
B. Capillary permeability
• determined by capillary structure and by the chemical nature of the
drug
• Capillary structure varies in terms of the fraction of the basement
membrane exposed by slit junctions between endothelial cells
• In the liver and spleen significant portion of the basement
membrane is exposed due to large, discontinuous capillaries through
which large plasma proteins can pass
• In the brain capillary structure is continuous, and there are no slit
junctions
• To enter the brain drugs must pass through the endothelial
cells of the CNS capillaries or be actively transported
• Eg: specific transporter carries levodopa into the brain
• lipid-soluble drugs readily penetrate the CNS because they
dissolve in the endothelial cell membrane
• Ionized or polar drugs generally fail to enter the CNS because
they cannot pass through the endothelial cells that have no
slit junctions
D. Lipophilicity
• chemical nature of a drug strongly influences its ability to cross cell
membranes
• Lipophilic drugs readily move across most biologic membranes
dissolve in the lipid membranes and penetrate the entire cell surface
• Major factor influencing the distribution of lipophilic drugs is blood
flow to the area
• hydrophilic drugs do not readily penetrate cell membranes and must
pass through slit junctions
E. Volume of distribution
• Apparent volume of distribution, Vd
• fluid volume that is required to contain the entire drug in the body at
the same concentration measured in the plasma
• calculated by dividing the dose that ultimately gets into the systemic
circulation by the plasma concentration at time zero (C0 )
1. Distribution into the water compartments
in the body:
• Once a drug enters the body has the potential to
distribute into any one of the three functionally
distinct compartments of body water or to become
sequestered in a cellular site
B. Apparent Volume of Distribution and
Physical Volumes
• Apparent volume of distribution (Vd) is an important pharmacokinetic
parameter that reflects the above determinants of the distribution of
a drug in the body
• Vd relates the amount of drug in the body to the concentration in the
plasma
Obesity alters the ratios of total body water to body weight and fat to
total body weight, and important when using highly lipid-soluble drugs
• Approximate rule for the aqueous compartments of the normal body
is as follows:
40% of total body weight is intracellular water
20% is extracellular water
water constitutes approximately 60% of body weight
Metabolism of Drugs
• Drug disposition refer to metabolism and elimination of drugs
• Metabolism of a drug sometimes terminates its action
• Some drugs when given orally are metabolized before they enter the
systemic circulation
• First-pass metabolism was one cause of low bioavailability
• Drug metabolism occurs primarily in the liver
A. Drug Metabolism as a Mechanism of
Activation or Termination of Drug Action
• Action of many drugs (sympathomimetics, phenothiazines) is
terminated before they are excreted because they are metabolized to
biologically inactive derivatives
• Conversion to an inactive metabolite is a form of elimination
• Prodrugs (levodopa, minoxidil) are inactive as administered and must
be metabolized in the body to become active
• Many drugs are active as administered and have active metabolites as
well (morphine, benzodiazepines)
B. Drug Elimination Without Metabolism
• Some drugs (lithium) are not modified by the body
• Continue to act until they are excreted
Elimination of Drugs
• Along with the dosage rate of elimination following the last dose
determines the duration of action for many drugs
Drug elimination is not the same as drug excretion:
A drug may be eliminated by metabolism long before the modified
molecules are excreted from the body
• For most drugs and their metabolite excretion is primarily by kidney
• Volatile anesthetic gases  excreted primarily by the lungs
• For drugs with active metabolites (diazepam) elimination of the parent
molecule by metabolism is not synonymous with termination of action
• For drugs that are not metabolized excretion is the mode of
elimination
• Some drugs combine irreversibly with their receptors, disappearance
from the bloodstream is not equivalent to cessation of drug action:
These drugs may have a very prolonged action
Phenoxybenzamine an irreversible inhibitor of α adrenoceptors,
eliminated from the bloodstream in less than 1 h after administration
• Drug’s action lasts for 48 h  time required for turnover of the
receptors
A. First-Order Elimination
• indicates that the rate of elimination is proportional to the
concentration (higher the concentration, the greater the amount of
drug eliminated per unit time)
• drug’s concentration in plasma decreases exponentially with time
• Drugs with first-order elimination have a characteristic half-life of
elimination that is constant regardless of the amount of drug in the
body concentration of such a drug in the blood will decrease by
50% for every half-life
B. Zero-Order Elimination
• implies that the rate of elimination is constant regardless of
concentration
• drugs that saturate their elimination mechanisms at concentrations of
clinical interest concentrations of these drugs in plasma decrease in
a linear fashion over time
• do not have a constant half-life
• Typical of ethanol (over most of its plasma concentration range) and
of phenytoin and aspirin at high therapeutic or toxic concentrations
 CLEARANCE
• Clearance (CL) relates the rate
of elimination to the plasma
concentration:
• For a drug eliminated with first-order kinetics clearance is a
constant ratio of rate of elimination to plasma concentration is the
same over a broad range of plasma concentration
Clearance depends on:
Drug
blood flow
condition of the organs of elimination
• Clearance of a particular drug by an individual organ is equivalent to
the extraction capability of that organ for that drug times the rate of
delivery of drug to the organ
• Clearance of a drug that is very effectively extracted by an organ
(blood is completely cleared of the drug as it passes through the
organ) is often flow-limited
• Total clearance from the body is a function of blood flow through
the eliminating organ and is limited by the blood flow to that organ
Cardiac disease, or other drugs that change blood flow—may have
more dramatic effects on clearance than disease of the organ of
elimination
Drugs eliminated with zero-order kinetics elimination rate is constant
and clearance is not constant
HALF-LIFE
• derived parameter
• completely determined by Vd and CL
• constant for drugs that follow first-order kinetics
• determined graphically from a plot of the blood level versus time or
from the following relationship:
HALF-LIFE
• Disease, age, and other variables usually alter the clearance of a drug
much more than they alter its Vd
• determines the rate at which blood concentration rises during a
constant infusion and falls after administration is stopped
• Effect of a drug at 87–90% of its steady-state concentration is clinically
indistinguishable from the steady-state effect
• 3–4 half-lives of dosing at a constant rate are considered adequate to
produce the effect to be expected at steady state
BIOAVAILABILITY
• is the fraction (F) of the administered dose that reaches the systemic
circulation
• defined as unity (or 100%) in intravenous administration
• Other routes generally reduced by incomplete absorption
(intestine, expulsion of drug by intestinal transporters), first-pass
metabolism
• Concentration appearing in the plasma is integrated over time to
obtain an integrated total area under the plasma concentration curve
(AUC)
1. Determination of bioavailability:
• Bioavailability is determined by comparing plasma levels of a drug
after a particular route of administration (oral administration) with
levels achieved by IV administration
• IV administration 100% of the drug rapidly enters the circulation
• drug is given orally only part of the administered dose appears in
the plasma
• By plotting plasma concentrations of the drug versus time area
under the curve (AUC) can be measured
• Total AUC reflects the extent of absorption of the drug
• Bioavailability of a drug given orally is the ratio of the AUC
following oral administration to the AUC following IV
administration (assuming IV and oral doses are equivalent)
2. Factors that influence bioavailability:
• In contrast to IV administration confers 100%
bioavailability, orally administered drugs often undergo first-
pass metabolism
• chemical and physical characteristics of the drug
determines the rate and extent to which the agent reaches
the systemic circulation
a. First-pass hepatic metabolism:
• When a drug is absorbed from the GI tract enters the portal
circulation before entering the systemic circulation
• If the drug is rapidly metabolized in the liver or gut wall during this
initial passage amount of unchanged drug entering the systemic
circulation is decreased
• Drugs with high first-pass metabolism should be given in doses
sufficient to ensure that enough active drug reaches the desired site
of action
b. Solubility of the drug:
• Very hydrophilic drugs are poorly absorbed because of their inability
to cross lipid-rich cell membranes
• Drugs that are extremely lipophilic are also poorly absorbed they
are totally insoluble in aqueous body fluids and cannot gain access
to the surface of cells
• For a drug to be readily absorbed must be largely lipophilic
c. Chemical instability:
• Some drugs, such as penicillin G, are unstable in the pH of the gastric
content
• Insulin destroyed in the GI tract by degradative enzymes
d. Nature of the drug formulation
• Drug absorption may be altered by factors unrelated to the
chemistry of the drug
• Eg: particle size, salt form, crystal polymorphism, enteric
coatings, and the presence of excipients (binders and
dispersing agents) can influence the ease of dissolution
alter the rate of absorption
D. Bioequivalence
• Two drug formulations are bioequivalent if they show
comparable bioavailability and similar times to
achieve peak blood concentrations
E. Therapeutic equivalence
• Two drug formulations are therapeutically equivalent if they
are pharmaceutically equivalent (have the same dosage
form, contain the same active ingredient, and use the same
route of administration) with similar clinical and safety
profiles
Pharmacokinetic Models
A. Multicompartment Distribution
• After absorption into the circulation many drugs undergo an early
distribution phase followed by a slower elimination phase
• a “two-compartment model”
• Two compartments consist of the blood and the extravascular tissues
Each phase is associated with a characteristic half-life:
t1/2α for the first phase
t1/2β for the second phase
• Elimination phase for a first-order drug is a straight line when plotted on a
logarithmic axis
B. Other Distribution Models
• A few drugs behave as if they were distributed to only 1 compartment
(restricted to the vascular compartment)
• Others have more complex distributions that require more than 2
compartments for construction of accurate mathematical models
PHARMACOGENOMICS
• Pharmacogenomics is a rapidly growing area of knowledge regarding
the genetic variations that influence drug metabolism and drug
effects
• Most of the research in this field to date has involved phase I or phase
II drug metabolism and drug transport
HUMAN LEUKOCYTE ANTIGEN (HLA)
POLYMORPHISMS

• HLA polymorphisms are associated with variations in immunologic

responses to drugs, including liver injury, Stevens-Johnson
syndrome, and toxic epidermal necrosis
• Polymorphisms have been associated with reactions to abacavir,
flucloxacillin, allopurinol, and carbamazepine
SELF ASSESSMENT QUIZ
1. Botulinum toxin is a large protein molecule. Its action on cholinergic
transmission depends on an intracellular action within nerve
endings. Which one of the following processes is best suited for
permeation of very large protein molecules into cells?
(A) Aqueous diffusion
(B) (B) Endocytosis
(C) (C) First-pass effect
(D) (D) Lipid diffusion
(E) (E) Special carrier transport
2. Ampicillin is eliminated by first-order kinetics. Which of the following
statements best describes the process by which the plasma concentration of
this drug declines?
(A) There is only 1 metabolic path for drug elimination
(B) The half-life is the same regardless of the plasma concentration
(C) The drug is largely metabolized in the liver after oral administration and
has low bioavailability
(D) The rate of elimination is proportional to the rate of administration at all
times
(E) The drug is distributed to only 1 compartment outside the vascular system
3.. The pharmacokinetics of a new drug are under study in a phase 1 clinical
trial. Which statement about the distribution of drugs to specific tissues is
most correct?
(A) Distribution to an organ is independent of blood flow
(B) Distribution is independent of the solubility of the drug in that tissue
(C) Distribution into a tissue depends on the unbound drug concentration
gradient between blood and the tissue
(D) Distribution is increased for drugs that are strongly bound to plasma
proteins
(E) Distribution has no effect on the half-life of the drug
4. The pharmacokinetic process or property that distinguishes the
elimination of ethanol and high doses of phenytoin and aspirin from
the elimination of most other drugs is called
(A) Distribution
(B) Excretion
(C) First-pass effect
(D) First-order elimination
(E) Zero-order elimination
• 1.1 An 18-year-old female patient is brought to the emergency
department due to drug overdose. Which of the following routes of
administration is the most desirable for administering the antidote for
the drug overdose?
• A. Intramuscular.
• B. Subcutaneous.
• C. Transdermal.
• D. Oral.
• E. Intravenous
• 1.3 Which of the following types of drugs will have maximum oral
bioavailability?
• A. Drugs with high first-pass metabolism.
• B. Highly hydrophilic drugs.
• C. Largely hydrophobic, yet soluble in aqueous solutions.
• D. Chemically unstable drugs.
• E. Drugs that are P-glycoprotein substrates.
• 1.4 Which of the following is true about the blood–brain barrier?
• A. Endothelial cells of the blood–brain barrier have slit junctions.
• B. Ionized or polar drugs can cross the blood–brain barrier easily.
• C. Drugs cannot cross the blood–brain barrier through specific
transporters.
• D. Lipid-soluble drugs readily cross the blood–brain barrier.
• E. The capillary structure of the blood–brain barrier is similar to that
of the liver and spleen.
• 1.7 Which of the following phase II metabolic reactions makes phase I
metabolites readily excretable in urine?
• A. Oxidation.
• B. Reduction.
• C. Glucuronidation.
• D. Hydrolysis.
• E. Alcohol dehydrogenation.