Pharmacokinetics

Chapters 8 and 11

1
 Pharmacokinetics and
pharmacodynamics
• Pharmacodynamics is the study of how
drugs interact with a molecular target, i.e;
effect of the drug on the body.
• 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 body2
 Pharmacokinetics &
related topics

The four main issues in

Pharmacokinetics are:
absorption, distribution, metabolism
and excretion

3
 Pharmacokinetics & related
topics

Drug absorption
• Refers to the route or method by which the
drug reaches the blood supply, this depends
on how the drug is administered.
• The most common and preferred method of
administration is the oral route.
• It depends on hydrophilic/hydrophobic
properties, polarity and ionization of the
drug.
4
 Drug absorption

I-Stability:
”Oral drugs have to be chemically stable to survive
the stomach HCl and metabolically stable to survive
the digestive enzymes in GIT and metabolic enzymes
in liver (mainly cytochrome P450 ).
-Insulin, local anaesthetics and first penicillins are
acid labile , so they can't be taken orally but are

given parentrally. 5
 Pharmacokinetics & related topics
Drug absorption
• II-Solubility
• The drug should have the correct balance of water
versus fat solubility
• Oral drugs should be sufficiently polar to dissolve
in the GIT and blood supply, but sufficiently fatty
to pass through the cell membranes (optimum
hydrophophobic/hydrophilic balance).
• Most oral drugs obey Lipinski’s rule of five, i.e.
1-A molecular weight less than 500
2-No more than 5 hydrogen bond donor groups
3-No more than 10 hydrogen bond acceptor groups
4-A calculated log P value less than + 5
6
 Pharmacokinetics & related topics
Drug absorption
• II-Solubility
A- Polarity:
• Some polar drugs break these rules are usually
poorly absorbed and have to be administered by
injection.
• Highly polar drugs will dissolve in GIT but they will fail to be
absorbed through the lipid cell membrane of the gut wall
while nonpolar drugs will be poorly soluble in the GIT instead
they will dissolve in the fat globules leading to poor surface
contact with cell membranes resulting in poor absorption ,
too. 7
Pharmacokinetics & related topics
Drug absorption
B-Ionization:
The presence of the weak ionizable -NH- group in
many drug structure would have three advantages:
A- good solubility due to =NH2+ cation in stomach
acid
B- good absorption due to conversion to non ionized
form in intestine in slightly alkaline pH
C-good target interactions
due to participation + H+ H
N H N
of ammonium ion in -H +
H

them
8
Drug absorption

-Henderson-Hasselbalch equation

pH= pKa + log [A-]/[HA]

C-Size :
Large molecular weight drugs generally have poor

absorption because they mostly have a large number

of polar groups which will lead to poor absorption of

these drugs.

9
 Pharmacokinetics & related topics
Drug absorption
mechanisms:
• Most drugs with proper solubility in
both water and lipid will be absorbed
through the lipid cell membrane of the
gut wall cells .
• Carrier proteins are essential to a cell’s
survival as they transport highly polar
building blocks required for various
biosynthetic pathways.
10
 Pharmacokinetics & related topics
Drug absorption mechanisms:
• Some polar drugs, are absorbed by special
carrier proteins such as levodopa
fluorouracil, lisinopril, methotrexate and
erythromycin, which are similar in structure
to (or bear a structural resemblance to) one
of the building blocks (such as amino acid)
then it too may be smuggled into the cell
• Other polar drugs with high molecular weight
are absorbed by pinocytosis (without passing
through the membrane).

11
 Pharmacokinetics & related topics
Drug absorption mechanisms:
• Some polar drugs with low molecular weight
(<200) are absorbed by passing through the pores
between cells lining the gut wall.
• Thus polar drugs are orally active if they are
small enough to pass between the cells of the
gut wall or are recognized by carrier proteins or
are taken across the gut wall by pinocytosis.
• N.B: sometimes drugs are designed to be highly
polar to be retained in the gut and not absorbed to
treat gut infections as some antibacterial agents
for gut infections. 12
 Pharmacokinetics & related topics
• Dosage:
• Drug dosing or dose regimen (regime) means drug
amount in each dose and frequency of administration.
• Due to the number of pharmacokinetic variables
involved, it can be difficult to estimate the correct
dosing regime for a drug.
• The drug should be administered at the correct dose
levels and at frequency to ensure that blood
concentration remain within the therapeutic window.
• Therapeutic window means drug levels in blood lie
between therapeutic and toxic levels). 13
Pharmacokinetics & related topics
• Dosage:
• In general, the concentration of free drug in blood
(non bound to plasma proteins) is a good indication
of the availability of that drug at its target site.

• Other dosing complications include differences in

age, sex, race, diet, environment, obesity, time of
dosing (due to change in metabolic rates throughout
the day), drug-drug interactions.

14
 Dosage

• The half-life of a drug is the time taken for the

blood concentration of the drug to fall by half. A
knowledge of half-life is required to calculate how
frequently doses should be given to ensure a
steady state concentration.

• Drug tolerance is where the effect of a drug

diminishes after repeated doses.
• In physical dependence a patient becomes
dependent on a drug and suffers withdrawal
symptoms on stopping the treatment. 15
 Formulation of drug
 Formulation refers to the method by which the drugs
are prepared for administration, where by solution,
pill, capsule, liposome (small vesicles consisting of a
phospholipid bilayer mambrane), or microsphere (small
spheres made up of a biologically degradable polymer
 The way a drug is formulated can avoid some of the
problems associated with oral administration.
 Drugs are normally taken orally as tablets or capsules.
 A tablet is a compressed preparation that contains 5-
10% of the drug (active ingredient), in addition to
many additives which help to ensure easy
disintegration, and dissolution of the tablet in the
stomach or intestine.
16
 Formulation of drug

 Tablet formulation can be modified to give rapid

effect (sublingual tablets) or sustained release.
Special coatings can make the tablet resistant to
stomach acid but disintegrates only in intestine
(enteric coated tablets).

Drug administration
• The main routes are oral, sublingual, rectal, topical,
epithelial, inhalation and injections. The method
chosen depends upon the target organ and the
pharmacokinetics of the drug.
17
 Methods (routes )of drug
administration
• Oral administration is the preferred method of
administering drugs, but it is also the most
demanding on the drug.
• Drugs administered by methods other than oral
route avoid the first pass effect
– Oral – Inhalation
– Sublingual – Injection
– Rectal • Intravenous
– Epithelial • Subcutaneous
• Topical • Intramuscular
• Nasal spray • Intrathecal
• Eyedrops
– Implants 18
 Drug administration
o Drugs can be administered such that they are
absorbed through the mucous membranes of the
mouth, nose, or eyes.
o Some drugs are administered rectally as
suppositories.
o Topically administered drugs are applied to the skin.
Some drugs are absorbed through the skin into the
blood supply.
o Inhaled drugs are administered as gases or aerosols
to act directly on the respiratory system. Some
inhaled drugs are absorbed into the blood supply to
act systemically. 19
 Drug administration

o Polar drugs which are unable to cross cell

membranes are given by injection.

o Injection is the most efficient method of

administering a drug but it also the most hazardous.
Injection can be intravenous, intramuscular,
subcutaneous, or intrathecal.

o Implants have been useful in providing controlled

drug release such that blood concentrations of the
drug remain as level as possible. (e.g. insulin, gliadel)
20
 Drug distribution
• Once the drug is absorbed, it is rapidly distributed
around the blood supply, then slowly distributed to
the various tissues and organs.
• Distribution to the interstitial fluid surrounding
tissues and organs is rapid if the drug is not bound
to plasma proteins .
• Some drugs have to enter cells in order to reach
their target.
• A certain percentage of a drug may be absorbed
into fatty tissue (e.g. Barbiturates) and/or bound
21
to macromolecules
 Drug distribution
• Drugs entering the CNS have to cross the blood-
brain barrier. Polar drugs (e.g. Penicillin) are
unable to cross this barrier unless they make use of
carrier proteins or are taken across by pinocytosis
(e.g. insulin).

• Some drugs cross the placental barrier into the

fetus and may harm development or prove toxic in
newborn babies (e.g. alcohol, nicotine, cocaine,
barbiturates)

22
 Drug-drug interactions
These are defined as the effects that one drug has on the
activity of another drug if both drugs are taken together.
Examples are Warfarin or methotrexate bound to albumin
and plasma protein in the blood and they will be
unavailable to interact with their targets.
When another drug is taken which can compete for plasma
protein binding (e.g. sulphonamide), then a certain
percentage of previously bound drug(warfarin or
methotrexate) is released, increasing the concentration
of the drug
and its
effect.

23
 Drug Metabolism
• Drugs are exposed to enzyme-catalyzed reactions
which modify their structure. This is called drug
metabolism and can take place in various tissues.
But, most reactions occur in liver.

• Orally taken drugs are subjected to the first pass

effect.

• Drugs administered by methods other than the

oral route avoid the first pass effect.

• Phase I metabolic reactions typically involve the

addition or exposure of a polar functional group. 24
 Drug Metabolism
• Cytochrome P450 enzymes present in the liver
carry out important phase I oxidation reactions.
The type of cytochrome P450 enzymes present
vary between individuals, leading to varying rates
of metabolism.
• The activity of cytochrome P450 enzymes can be
affected by food, chemicals, and drugs, resulting in
drug-drug interactions and possible side effects.

• Phase II metabolic reactions involve the addition

of highly polar molecules to a functional group. The
resulting conjugate are more easily excreted.
25
 Drug Excretion
• Drugs excretion can take place through sweat,
exhaled air, or bile, but most excretion takes place
through the kidneys.

• The kidneys filter blood such that drugs and their

metabolites enter nephrons.
• Non-polar substances are reabsorbed into the
blood supply, but polar substances are retained in
the nephrons and excreted in urine.

26
To control chemical and
physical properties…

• Drug design
• Alter functional groups
• Quantitative SARs
• Computational methods

27
 Solubility
• Hydrophobic/hydrophilic balance:
• The hydrophobic/hydrophilic character of the drug is the crucial
factor affecting absorption through the gut wall.
• Decrease polarity
By masking a polar functional O

or
group with an alkyl or acyl group.
R OH R OR' R O C R'

O O

R C OH R C OR'

• Increase polarity
By adding a polar or Cl
S

More polar N
N

functional group Cl F
N

to a drug to increase its O N

polarity.
N N
N N

Cl H F HO

• Ionization (I)Ticonazole -----------------------(II)Fuconazole

28
 Stability
• Option A: Make drugs more resistant to
metabolism and hydrolysis
1. Steric shield
• Some functional groups are susceptible to
chemical and enzymatic degradation than others.
• To protect such groups, a steric shield designed
to hinder the approach of a nucleophile or
enzyme to those groups is added.
• These usually involve the addition of a bulky
alkyl group close to the functional group. E.g., t-
butyl group. O O

R R' R R'
O O

CH3 C CH3
29
CH3
 Stability
O O

C R C R

2- Bioisosteres
CH3 O H2N O

 To protect a labile functional group by

stabilizing it electronically using a bioisostere.
 Using bioisostere is to replace a chemical group
within the drug with another chemical group (of
the same size and valency but with different
electronic property) without affecting the
important biological activity. This may also
improve drug’s stability.
30
 Stability
3- Stereo electronic modification
 This means steric hinderance together with
electronic stabilization are used stabilize labile
groups.
 Example: lidocaine from procaine
 Proocaine is short lasting due to quick hydrolysis
of its ester group. Changing this ester group into
less reactive amide reduces chemical hydrolysis.
 Moreover, the presence of two o-methyl groups
on aromatic ring provides a steric shield for the
carbonyl group. O
O Lidocaine
N
N NH
O
CH3 CH3

Proocaine or NH2 31
novocaine
 Stability
4. Metabolic blockers
 Example: R R'
Ox
R R'

Some drugs are

metabolized by the OH

introduction of polar
groups at particular
positions in their
R R' Ox

skeleton.
Megestrol acetate is
CH3

oxidized at position 6 to
give a hydroxyl group, O

leading to quick O O

elimination of the water H

soluble conjugate.
By introducing a methyl
H H

group in its analogue at
O

this position, metabolism

is blocked and its action
is prolonged. Megestrol acetate analogue
32
 Stability
5. Remove metabolic
groups
• Certain chemical groups are CH3 CO2H
susceptible to metabolic Ox
enzymes.
• Example: CH3-group on
aromatic ring are often OH

oxidized into –COOH, which Ox

can be quickly eliminated

from the body.
• These groups are either Cl

removed or replaced by Ox

groups that are stable to

oxidation to prolong the
lifetime of the drug.
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 Stability
5. Remove metabolic groups
Chlorpropamide from tolbutamide
CH3 group was replaced by Cl atom and action is
more prolonged.

O O

H3C S NH Cl S NH

O NH O NH

O O

Tolbutamide Chlorpropamide
34
 Stability
6. Group Shifts
OH OCH3
metabolize

OH metabolize

When a vulnerable chemical group can’t be replaced

or removed because it is involved in important
binding interactions with the binding site, we have
two possible solutions.
One is to mask this group temporarily by using a
prodrug. The second is to try shifting this group
within the molecular skeleton.
35
 Stability
6. Group Shifts
Example: Salbutamol from noradrenaline, where in
noradrenaline, both phenolic groups are involved in
hydrogen bonding to the receptor, thus
metabolic methylation of one of these groups makes
the compound inactive and has a short duration.
A solution is to move one phenolic group out from the
ring by one carbon unit only (if more, activity is
lost, due to improper binding) OH
Salbutamol
HO

OH OH

HO HO

NH2 NH 36
Noradrenaline C(CH3)3
 Stability

• Option B: Make drugs less resistant to

metabolism:
• A drug that is extremely stable to metabolism
and is very slowly excreted can pose just as
many problems as one that is susceptible to
metabolism.
• If the effects of the drug could last too long
then it would cause both:
→ Toxicity
→ Lingering side effects
Therefore, designing drugs with decreased
chemical and metabolic stability can sometimes
be useful. This is called shortening the lifetime
of the drug. 37
 Other factors in drug design

• Reducing Toxicity:
• A drug fails clinical trials because of its toxic side
effects. This may be due to toxic metabolites.

• Thus, the drug should be made more resistant to

metabolism by knowing functional groups prone to
producing toxic metabolites and removing them or
changing them into harmless substituents or
varying their position.

38
 Other factors in drug design
O

• Prodrugs:
• Prodrugs are inactive
N
N

compounds but which are

converted in the body into
the active drug
Cl

• I-Valium (more sustained action) Valium N-demethylation

→ nordazepam: O
• Valium sedative is believed
to be a prodrug and is H
metabolized by N-
N
N

demethylation into
Nordazepam. The latter
has been used as a
sedative, but loses activity
by metabolism and Cl

excretion. Nordiazepam 39
 Other factors in drug design
• Prodrugs:
II-L-dopa → dopamine (approach for carrier
protein):
prodrug---→ active drug
– Levodopa is a prodrug for the neurotransmitter
dopamine which is used in Parkinson’s disease.
levodopa is much more polar than dopamine but
yet it can cross the BBB because it is an amino
acid and is recognized by the carrier proteins
for amino acids.
NH2 HO NH2 HO NH2

O OH HO O OH HO

phenylalanine levodopa dopamine 40

 Other factors in drug design
• Prodrugs:
III-Aspirin → salicylic acid:
To mask drug toxicity and side effects
Salicylic acid is a good painkiller but causes
gastric bleeding due to phenolic OH which is
converted into an ester in aspirin. The ester is
later hydrolysed to free the active drug.
O

O OH

O O

OH OH
aspirin salicylic acid

Also, aspirin is an antiinflammatory action.

41
 Sentry drugs
A second drug is administered alongside the principal drug
where the role of the second drug is to guard or assist
the principal drug.
L-DOPA DOPAMINE
1- Carbidopa: ENZYME

Levodopa is a prodrug for dopamine

INHIBITION
but large doses are required
to be effective due to its HO
C
NHNH2

Decarboxylation before it reaches HO

Me CO2H

the CNS .
Carbidopa is an inhibitor
of dopa decarboxylase
And thus it allows smaller doses of levodopa to be used with
lower side effects. Furthermore, carbidopa is highly
polar so it can’t pass BBB where the decarboxylation of
levodopa is required.
42
 • Sentry drugs
2- Clavulanic acid and amoxicillin
O

O O O

R O
N
OH
HN N
H OH
O
H
H
S

OH

Clavulanic acid inhibits the enzyme β-

lactamase in microorganisms and is therefore
able to protect penicillins (amoxicillin) from
that particular microbial enzyme.

43