PHARMACOKINETICS

SUN YI

Department of Pharmacology

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 OVERVIEW

• Pharmacokinetics :

refer to what the body dose to a drug

Once administered through one of several

available routes, four pharmacokinetic properties
determine the speed of onset of drug action, the
intensity of the drug’s effect, and the duration of
drug action .

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Drug at site of administration Disposition: ADME

Absorption(input) Transport: ADE

Drug in plasma Elimination: ME

Distribution
Drug in tissues
Metabolism
Metabolism(s) in tissues
Excretion(output)

Drug and/or metabolite(s) in

urine, bile, or feces 3
DRUG TRANSPORT

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• Passive diffusion
moves from a region of high concentration to one of
lower concentration
no energy
no carriers
not saturable
non-competitive
low structural specificity

extracellular

intracellular

Water-soluble drug Lipid-soluble drug 5

• Facilitated diffusion
enter the cell through specialized transmembrane carrier
proteins that facilitate the passage of large molecules.
move from high concentration to an area of low
concentration
energy-independent
saturable
competive

extracellular

intracellular

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• Active transport
involve specific carrier proteins
moves drug against a concentration gradient
energy-dependent
saturable
can be competitively inhibited by other
cotransported substances

ATP ADP
extracellular

intracellular

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• endocytosis and exocytosis
Endocytosis involves engulfment of a drug
molecule by the cell membrane and transport into
the cell by pinching off the drug-filled vesicle.
Transport drugs of exceptionally large size

extracellular

intracellular

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ROUTES OF ADMINISTRATION

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• Enteral
Safest, most common, convenient, economical
①Oral
②Sublingual

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 glyceryl trinitrate，
Nitroglycerin(GTN):

• Bioavailability:<1%
• Metabolism: liver, red blood
cells, vascular wall
• Half-life: 3 min
• Excretion: urine, bile
• Different forms of
nitroglycerin: tablets,
intravenous, spray and patch.

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Intramuscular Intracutaneous
• Parenteral Subcutaneous
Intravenous

Epidermis
Genuine leather
Subcutaneous tissue
muscle

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IM SC IV IC
• Others
Oral inhalation
Nasal inhalation
Intrathecal/intraventricular

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• Others
Cream
Topical
Transdermal
Rectal
Lotion

Fentanyl Transdermal Patch

Antipyretic suppository
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• Drug Delivery Systems

Enteral: Parenteral:
Powder Injection spray
Tablets Drops
Granules Patch
Capsules Ointment
Emulsion
Suspension

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ABSORPTION

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 ABSORPTION
• the transfer of a drug from its site of administration
to the bloodstream via one of several mechanisms.

• depends on
the environment where the drug is absorbed
the drug’s chemical characters
the route of administration
For IV delivery, bioavailability is 100%. Drug delivery
by other routes may result in only partial absorption
and, thus, lower bioavailability.
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• Factors influencing absorption

① pH

A low pH inhibits ionization of a weak acid and

enhances its absorption across a membrane. So weak
acids are best absorbed in the stomach.

A high pH inhibits ionization of a weak base and

enhances its absorption across a membrane. So alkalinic
drugs are best absorbed in the small intestine.

Stomach: azithromycin
Intestine: metformine

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②blood flow to the absorption site
Intestine>stomach

③ total surface area available for absorption

Intestine>stomach

④contact time at the absorption surface

Anything that delays the rate of absorption of the
drug from the stomach to the intestine delays the
rate of absorption of the drug.
Meal, diarrhea
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⑤ Expression of P-glycoprotein

A multidrug trans-membrane transporter protein

responsible for transporting various molecules.

Liver: transporting drugs into bile for elimination

Kidney: pumping drug into urine for excretion
Placenta: transporting drug back into maternal blood,
thereby reducing fetal exposure to drugs
Intestine: transporting drug into the intestinal lumen
and reducing drug absorption into the blood
Brain capillaries: pumping drug back into blood,
limiting drug access to the brain
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⑥First pass effect
When a drug is absorbed across the GI tract, it first
enters the portal circulation before entering the
systemic circulation. If the drug is rapidly metabolized
in the liver or gut wall during its initial passage, the
amount of unchanged drug that gains access to the
systemic circulation is decreased.
It is a phenomenon of drug metabolism whereby
the concentration of a drug is greatly reduced before it
reaches the systemic circulation. It is the fraction of
drug lost during the process of absorption which is
generally related to the liver and gut wall.
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 The four primary systems that affect the first pass
effect of a drug are the enzymes of the gastrointestinal
lumen, gut wall enzymes, bacterial enzymes, and
hepatic enzymes.
limit the efficacy of many drugs when taken orally
Change the administration route
Morphine, pethidine, midazolam, lidocaine, and
nitroglycerin.

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⑦Drug-drug interaction
solubility
pH
complex
absorption
inhibition of the activation of prodrug
competition of the same transport
changing the gastric emptying and gastrointestinal
motility

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⑧Dosage form

⑨Route of administration

IV

inhalation>sublingual>rectal>IM>SC> oral

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DISTRIBUTION

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 DISTRIBUTION

• the drug may then reversibly leave the

blood-stream and enters the interstitial and
then the cells of the tissues
• depends on how soluble the drug molecule
is in fat (to pass through membranes) and on
the extent to which the drug binds to blood
proteins (albumin)

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• Perfusion rate
Brain, liver, kidney > skeletal muscles

• Diffusion rate
Barrier, the chemical nature of the drug

• Binding of drug to plasma proteins and tissue

proteins

• Redistribution

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• Redistribution
Highly lipid-soluble drugs given by intravenous or
inhalation routes are initially distributed to organs
with high blood flow. Later, less vascular but more
bulky tissues (such as muscle and fat) take up the
drug-plasma concentration falls and the drug is
withdrawn from these sites.
If the site of action of the drug was in one of the
highly perfused organs, redistribution results in
termination of the drug action.
The greater the lipid solubility of the drug, the
faster its redistribution will be.
thiopental sodium
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• Blood-Brain Barrier(BBB)
It is a highly selective semipermeable membrane
barrier that separates the circulating blood from the
brain and extracellular fluid in the central nervous
system (CNS).
Blood brain barrier is a barrier between plasma
and brain cells formed by brain capillary wall and glial
cells.
This barrier provides a protective environment for
the brain.
Speed of transport across this barrier is limited by
the lipid solubility of the psychoactive molecule.

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• Placental Barrier
The placenta is an organ that connects the
developing fetus to the uterine wall to allow nutrient
uptake, thermo-regulation, waste elimination, and
gas exchange via the mother's blood supply; to fight
against internal infection; and to produce hormones
which support pregnancy.

This barrier separates two

distinct human beings but is
very permeable to lipid
soluble drugs.
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• Blood-testis barrier/ Sertoli cell barrier (SCB)
The fluid in the lumen of seminiferous tubules is
quite different from plasma; it contains very little
protein and glucose but is rich in androgens, estrogens,
potassium, inositol and Glutamic and Aspartic acid. This
composition is maintained by blood–testis barrier.
The barrier also protects the germ cells from blood-
borne noxious agents, prevents antigenic products of
germ cell maturation from entering the circulation and
generating an autoimmune response, and may help
establish an osmotic gradient that facilitates movement
of fluid into the tubular lumen.
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• Blood-ocular barrier
The blood–ocular barrier is a barrier created by
endothelium of capillaries of the retina and iris,
ciliary epithelium and retinal pigment epithelium.
It is a physical barrier between the local blood
vessels and most parts of the eye itself, and stops
many substances including drugs from traveling
across it.
Inflammation can break down this barrier
allowing drugs and large molecules to penetrate into
the eye.

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METABOLISM

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 METABOLISM
• biotransformed by metabolism by the liver or other tissue

CYP
Oxidation
Drug Phase I Reduction Phase II Conjugation
hydrolysis products

Inactivated
Activated Inactivated
Toxic
Prodrugs 34
• Cytochrome P450 (CPY)

• Heme-containing isozymes
• Located in most cells but are primarily in the liver
and GI tract
• Exhibit considerable genetic variability
• Polymorphisms
• Low specificity
• Limited activity
• CYP3A4
• Enzyme Induction & Enzyme Inhibition

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• Enzyme Induction & Enzyme Inhibition : Many drugs
may increase or decrease the activity of various CYP
isozymes either by inducing the biosynthesis of an
isozyme (enzyme induction) or by directly inhibiting
the activity of the CYP (enzyme inhibition)

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 Chlorphenamine maleate

CNS inhibition Anti histamine

↓
BBB Ketoconazole
↓ Erythromycin
Cimetidine
Chemical structure
modification - Enzyme
inhibition
↓
CYP3A4
Terfenadine Terfenadine acid
Prodrug ↓
Fexofenadine
Cardiotoxicity hydrochloride 37
ELIMINATION

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 ELIMINATION
• the drug and its metabolites are eliminated from the
body
• Requires the agents to be sufficiently polar for
efficient excretion
• Routes of elimination
Kidney: glomerular filtration, active tubular
secretion, passive reabsorption
Intestine: feces
Bile: biliary excretion, enterophepatic cycle
Milk in nursing mothers

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• Drug clearance
by the kidney

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• Glomerular filtration will only remove those drugs or
metabolites that are not bound to proteins present
in blood plasma (free fraction) and many other types
of drugs (such as the organic acids) are actively
secreted.
• Tubular reabsorption is the process by which solutes
and water are removed from the tubular fluid and
transported into the blood.

• In the proximal and distal convoluted tubules non-

ionised acids and weak bases are reabsorbed both
actively and passively.
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• Enterohepatic circulation
the circulation of biliary
acids, bilirubin, drugs, or
other substances from the
liver to the bile, followed by
entry into the small
intestine, absorption by the
enterocyte and transport
back to the liver.
Duration of drug ↑
Accumulation of toxin ↑
theophylline,
phenobarbital, and
phenytoin 42
• Levodopa: kidney
• Zolpidem: intestine + kidney
• Indomethacin: bile + intestine + kidney
• Diazepam: kidney +milk in nursing mothers
• Morphine: kidney +milk in nursing mothers
• Cimetidine: kidney +milk in nursing mothers
• Zopiclone: intestine + kidney+saliva+milk in
nursing mothers
• respiratory tract : alcohol or anaesthetic gases.

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PARAMETER

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• Drug concentration-time curve

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• Bioavailability
Is the fraction of administrated drug that reaches the
systemic circulation
①Determination
the relative rate and extent to which an administered
drug reaches the general (systemic) circulation
the absorption and the preparation of a drug

AUC oral
Bioavailability = ×100%
AUC injected

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 ②Factors
 Physical properties of the drug
hydrophobicity, pKa, solubility
 Nature of the drug formulation
Particle size, salt form, crystal polymorphism, enteric
coatings, the presence of excipients
 Whether the formulation is administered in a fed or
fasted state
 Circadian differences
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 Physical state

GI tract, liver, kidney

 Enzyme induction/inhibition by other drugs/foods

 Interactions with other drugs/foods

 Transporters

 First-pass effect

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• Bioequivalence
Two related drug preparation are bioequivalent if
they show comparable bioavailability and similar
times to achieve peak blood concentration.

• Therapeutic equivalence
Two similar drug products are therapeutically equal if
they are pharmaceutically equivalent with similar
clinical and safety profiles.

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• Half life, t1/2
the time it takes for a drug to lose one-half of its
pharmacologic activity
the time required for the drug concentration to
change by 50 percent
the speed of drug elimination
to determine the dosing interval
3.3 t1/2 →90%， 6.6 t1/2 →99%

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• Clearance, Cl
the volume of plasma from which a substance is
completely removed per unit time

the usual units are mL/min

reflect the ability of the body to eliminate the drug

determine the dosage

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 KEY POINT

• Drug transport
• Administration route
• First-pass effect
• CYP
• Enzyme Induction & Enzyme Inhibition
• Enterohepatic cycle
• Half life
• Clearance
• Bioavailability

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