PHARMACOKINETICS

“What the body does to the drug”

 DEFENITION
Pharmacokinetics is defined as the kinetics of drug
absorption, distribution, metabolism and excretion
(KADME) and their relationship with the
pharmacological, therapeutic or toxicological
response in man and animals.

Pharmacokinetics is the quantitative study of

drug movement in, through and out of the body.
Intensity of effect is related to the concentration
of the drug at the site of action, which depends
on its pharmacokinetic properties.
Pharmacokinetics is the study of how a drug
reachs 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 (PK)

 The study of the disposition of a drug

 The disposition of a drug includes
the processes of ADME
 Absorption

 Distribution
 Metabolism
Elimination
 Excretion
 Toxicity
ADMET
 DRUG R&D

Drug discovery and development

•10-15 years to develop a new medicine
•Likelihood of success: 10%
•Cost $800 million – 1 billion dollars (US)
Why drugs fail
 Importance of PK studies

 Patients may suffer:

 Toxic drugs may accumulate

 Useful drugs may have no benefit

because doses are too small to
establish therapy

 A drug can be rapidly metabolized.

 Routes Of
Administration

Routes Of Drug
Administration

Parenteral Enteral

Injection Topical Respiratory Rectal Oral

 Absorption
 The process by which drug proceeds from
the site of administration to the site of
measurement (blood stream) within the
body.

 Necessary for the production of a

therapeutic effect.

 Most drugs undergo gastrointestinal

absorption. This is extent to which drug is
absorbed from gut lumen into portal
circulation
 Exception: IV drug administration
 IV vs Oral

I.V Drug Oral Drug

Immediately Delayed

completely incomplete
 The Process
 Absorption relies on
 Passage through membranes to reach the
blood
 passive diffusion of lipid soluble species.
Absorption
 Transport Mechanism

 Passive transport
 - Passive diffusion
 - Filtration

 Specialized transport
 - Carrier transport
 Active transport
 Facilitated diffusion
 - Pinocytosis, etc.

Convection
 The Rule of Five -
formulation
Poor absorption or permeation are
more likely when:

 There are more than 5 H-bond donors.

 The molecular weight is over 500.
 The LogP is over 5.
 There are more than 10 H-bond
acceptors.
 Cara absorpsi obat/ mekanisme transport :
1. Difusi pasif / sederhana/ non ionik

 Ciri – Ciri :
1. Arah transport searah dg perbedaan kadar /
gradient kadar
 C1 > C2
 C1 = C2 = transport berhenti
 yg dapat menembus membran adlh obat
bebas
 Zat lipofil lebih mudah larut daripada zat
hidrofil.
 C1 & C2 = kadar obat yg dapat menembus
membrane
2. Keadaan setimbang tercapai jika kadar obat
yg dapat menembus membrane di ke-2 sisi
membrane sama.
Kecepatan transport tergantung konsentrasi
obat.
3. Kecepatan penetrasi / difusi untuk elektrolit
lemah dipengaruhi oleh pH lingkungan.
HA→H(+) + A(-) HA : elektrolit
lemah
α<1 α : derajat ionisasi
 Next to the other PPT
 FILTRATION
 Filtration is passage of a drug through aqueous
pores in the membrane through paracelullar
spaces.
 The filtration has an importance mainly at the level
of renal glomerulus, where the size of capillaries
have large pores (40 Å) and most drugs (even
albumin) can filtrate. The brain capillary pores have
small size.
Absorption & Ionization
Non-ionised
drug

More lipid soluble drug

Diffuse across
cell
membranes more
easily
 First Pass Metabolism

Destroyed Not Destroyed Destroyed

in gut absorbed by gut wall by liver

to
Dose systemic
circulation

 Bioavailability: the fraction of the administered dose

reaching the systemic circulation
 Determination of
bioavailability
 A drug given by the
intravenous route will have
an absolute bioavailability
of 1 (F=1 or 100%
bioavavailable)

 While drugs given by other

routes usually have an
absolute bioavailability of
less than one.

.
 The absolute bioavailability
is the area under curve (AUC)
non-intravenous divided by
AUC intravenous
 Toxicity
 The therapeutic
index is the degree
of separation
between toxic and
therapeutic doses.

 Relationship
Between Dose,
Therapeutic Effect
and Toxic Effect.
The Therapeutic
Index is Narrow for 100× 10×
Most Cancer Drugs
 Distribution
 The movement of drug from the blood
to and from the tissues
 DISTRIBUTION
 Determined by:
 • partitioning across various membranes

 •binding to tissue components

 •binding to blood components (RBC,

plasma protein)

 •physiological volumes
 DISTRIBUTION
 All of the fluid in the body (referred to as the total
body water), in which a drug can be dissolved, can
be roughly divided into three compartments:

 intravascular (blood plasma found within blood

vessels)
 interstitial/tissue (fluid surrounding cells)
 intracellular (fluid within cells, i.e. cytosol)

 The distribution of a drug into these compartments

is dictated by it's physical and chemical properties
 TOTAL BODY WATER
Vascular Extravascular Intracellular

3L 9L 28 L

4% BW 13% BW 41% BW
 Distribution
 Apparent volume of distribution (Vd) =

Amt of drug in body/plasma drug conc

 VOLUME OF DISTRIBUTION FOR SOME DRUGS

DRUG Vd (L)
cocaine 140
clonazepam 210
amitriptyline 1050
amiodarone ~5000
 Factors affecting drugs Vd
 Blood flow: rate varies widely as function of tissue
Muscle = slow
Organs = fast

 Capillary structure:
•Most capillaries are “leaky” and do not impede diffusion
of drugs
•Blood-brain barrier formed by high level of tight
junctions between cells
•BBB is impermeable to most water-soluble drugs
 Blood Brain Barrier

•Disruption by osmotic
means
•Use of endogenous
transport systems
•Blocking of active
efflux transporters
• Intracerebral
implantation
•Etc
 Plasma Protein Binding

 Many drugs bind to plasma

proteins in the blood steam

 Plasma protein binding limits

distribution.

 A drug that binds plasma protein

diffuses less efficiently, than a drug
that doesn’t.
 Physiochemical properties-
Po/w

 The Partition coefficient (Po/w) and can be

used to determine where a drug likes to go
in the body
 Any drug with a Po/w greater than 1(diffuse
through cell membranes easily) is likely be
found throughout all three fluid
compartments
 Drugs with low Po/w values (meaning that
they are fairly water-soluble) are often
unable to cross and require more time to
distribute throughout the rest of the body
 Physiochemical Properties-
Size of drug

•The size of a drug also dictates where it can go in the body.

•Most drugs : 250 and 450 Da MW

•Tiny drugs (150-200 Da) with low Po/w values like caffeine can
passively diffuse through cell membranes

•Antibodies and other drugs range into the thousands of daltons

•Drugs >200 Da with low Po/w values cannot passively cross

membranes- require specialized protein-based transmembrane
transport systems- slower distribution

•Drugs < thousand daltons with high Po/w values-simply diffuse

between the lipid molecules that make up membranes, while
anything larger requires specialized transport.
 Elimination
 The irreversible removal of the
parent drugs from the body
Elimination

Excretion Drug Metabolism

(Biotransformation)
 Drug Metabolism
 The chemical modification of drugs with
the overall goal of getting rid of the drug
 Enzymes are typically involved in
metabolism

Metabolism Excretion
More polar
Drug
(water soluble)
Drug
 METABOLISM
•From 1898 through to 1910 heroin was marketed as a non-
addictive morphine substitute and cough medicine for
children. Bayer marketed heroin as a cure for morphine
addiction
•Heroin is converted to morphine when metabolized in the
liver
 Phases of Drug Metabolism
 Phase I Reactions

 Convert parent compound into a more polar

(=hydrophilic) metabolite by adding or
unmasking functional groups (-OH, -SH, -NH2, -
COOH, etc.) eg. oxidation

 Often these metabolites are inactive

 May be sufficiently polar to be excreted readily

 Phases of metabolism
 Phase II Reactions

 Conjugation with endogenous substrate to

further increase aqueous solubility

 Conjugation with glucoronide, sulfate,

acetate, amino acid
 Mostly occurs
in the liver
because all of
the blood in the
body passes
through the
liver
 The Most Important
Enzymes

 Microsomal cytochrome P450

monooxygenase family of enzymes, which
oxidize drugs

 Act on structurally unrelated drugs

 Metabolize the widest range of drugs.

 CYP family of enzymes

•Found in liver, small intestine, lungs, kidneys,

placenta

• Consists of > 50 isoforms

• Major source of catalytic activity for drug oxidation

• It’s been estimated that 90% or more of human drug

oxidation can be attributed to 6 main enzymes:
• CYP1A2 • CYP2D6
• CYP2C9 • CYP2E1
• CYP2C19 • CYP3A4

Indifferent people and different populations,

activity of CYP oxidases differs.
 Inhibitors and inducers of
microsomal enzymes

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

Blockers:
acting on non-microsomal
enzymes (MAOI, anticholinesterase drugs)
 Phase II

 Main function of phase I reactions is to

prepare chemicals for phase II
metabolism and subsequent excretion

 Phase II is the true “detoxification”

step in the metabolism process.
 Phase II reactions

 Conjugation reactions

 Glucuronidation (on -OH, -COOH, -NH2, -SH groups)

 Sulfation (on -NH2, -SO2NH2, -OH groups)

 Acetylation (on -NH2, -SO2NH2, -OH groups)

 Amino acid conjugation (on -COOH groups)

 Glutathione conjugation (to epoxides or organic

halides)

 Fatty acid conjugation (on -OH groups)

 Condensation reactions
 Glucuronidation
 Conjugation to a-d-glucuronic acid

 Quantitatively the most important phase II pathway for

drugs and endogenous compounds

 Products are often excreted in the bile

 Phase I and II - Summary

 Products are generally more water soluble

 These reactions products are ready for (renal) excretion

 There are many complementary, sequential and

competing pathways

 Phase I and Phase II metabolism are a coupled

interactive system interfacing with endogenous
metabolic pathways
 Excretion
 The main process that body eliminates
"unwanted" substances.

 Most common route - biliary or renal

 Other routes - lung (through exhalation),

skin (through perspiration) etc.

 Lipophilic drugs may require several

metabolism steps before they are
excreted
ADME - Summary