Department

of Pharmaceutical Chemistry WHAT HAPPENS TO THE DRUG IN THE BODY-

College of Pharmacy PHARMACOKINETICS
Jazan University, Jazan, KSA
PHARMACEUTICAL CHEMISTRY II TA

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PHYSICO-CHEMICAL PROPERTIES OF ①
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DRUGS IN RELATION TO BIOLOGICAL

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Chapter 2 – Part 1 f y
per
v

‫وضعنا‬

G
,
,j

By ←

Prof.Neelaveni Thangavel e.im :÷÷÷÷÷÷÷÷÷÷÷÷÷÷÷:÷÷f

Gwin.*.co.in.
⇐
Profanities I kiss ' -

Cinitravenonssjvein
.im#iiw..e*.iedkJlikA/.obsIew
.

He Is
wisdom
8/26/2020 New course, version 1 1 8/26/2020 New course, version 1 2
.

• A drug is a chemical molecule. • The ability of a drug to elicit a

• Following introduction into the body, #
pharmacological/ therapeutic effect is

#⇐I_)
- related to the influence of various physical

Is
a drug must pass through many and chemical (physicochemical) properties.
barriers, survive alternate sites of • These physico-chemical properties influence
¥9
attachment and storage and avoid
-

pharmacological activities by affecting

metabolic destruction before it =
various pharmacokinetic phenomenon in
reaches to the site of action (usually vivo, such as: absorption, distribution,
receptor on or in a cell). ÷÷÷÷÷÷÷÷÷÷÷÷÷÷÷:c metabolism and excretion.

soon
8/26/2020
,
New course, version 1 3 8/26/2020 New course, version 1 4
 7%77 body solvent Present water and pipe'd
the the main is .

HI #signs , extravascular spaces

SOLUBILITY
,

{Most important physiochemical properties of

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.

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① j
-

# -

www.IH b'In sat

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!!
j.gs#6fsIiw@sIscmsd m
.

drugs affecting biological activities

I
WI # is
* eh , Itis #
WH It
II. is
.

JI .

• Solubility is the characteristic physical property

• Solubility

]⇐÷÷÷÷÷÷÷¥÷÷
÷w :# swim .

referring to the ability of a given substance, ie

Mta# 10¥ ,
if E@

did
Pharmacokinetic

Partition coefficient
>

•
.

the solute, to dissolve in a solvent

①
• Ionization constant and pKa •§Polar drugs are water soluble or
drugs Nora Polar soluble

Hydrogen bonding • Non polar drugs are water insoluble

are

• I + in lipid .

• Isosterism and Bioisosterism • hydrophilic....................water

water loving ✓
soluble in

Be what
or list
are the Physicochemical

the u l'
properites . . . - .
• lipophobic.....................lipid
Hill UHM 161A Kkk hating
n

←
• lipophilic.......................lipid
soluble lipid loving ✓in

fB
-

Tsim

• hydrophobic..................water hating ✓ M as he

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type of drug
• Solubility of drugs in aqueous (water) and lipid phases of
what

a*
will be Polar

a an
or or
y y,

a) Water solubility (or hydrophilicity)depends on two

*
the body is important in maintaining the concentrations ÷

¥T¥w
of drugs at their site of action and hence its factors , } a #, Me .

of * ÷.
②

effectiveness. • Ionic character and hydrogen bonding capabilities Whit

aw¥÷o
00
0#n#¥""¥id÷
• Solubility affects absorption, diffusion and partition of Water solubility is required for
"

or
egads ÷÷÷÷÷÷÷÷÷ , . ⇐
**
car,

drug molecules between aqueous phase and the cell •*Dissolution in the GIT
%÷±÷ * ÷. :* .

membrane (lipoidal in nature). ‫تؤثر القابلية للذوبان على امتصاص وانتشار‬

‫اليل الوريدية‬O‫ضير ا‬M oIs&2&
• Preparation of parentral solutions
‫ائي‬H‫وتقسيم جزيئات الدواء بي الطور ا‬ Tommi § All
‫لية‬L‫وغشاء ا‬
• Hence, a correct balance of water and lipid solubilities is
.

needed for the passage of drugs through various =

• Preparation of ophthalmic solution
membranes. as ÷: • To be effective, most drugs have to be administered
• A drug’s solubility depends on the chemical structure of
the compound and the - nature of the solvent as well as
Iffy
in dosage forms that are water-soluble.
-

• Also drug’s distribution through the circulatory

MtDNAtney ,n?
2-

temperature, pressure, and pH. intortant factor .

system, and
-
HLINKA hence its action, depend toWKUsome extent
MSS

1E÷÷÷
on it having a reasonable water solubility.
-

inside

8/26/2020 New course, version 1 7 8/26/2020 .

New course, version 1 8
 what type of drugs will be soluble in lipid ?
or when the
• Example. In a homologous series of alcohols, the lower
b)Lipid solubility (or lipophilicity)is increased by
TT if it has members of series show less bactericidal activity and with
increasing the STI hydrocarbon chain and ring
-

increase in length of carbon chain (nonpolar) the activity

.

systems in the drug’s structure.

*.

t Fg's !
hydrophilic f. IT
Ill like
→ '" I ↳

d Polar functiondope
* increases to a maximum.
the only reason

• Lipid solubility is required for: Butanol< Pentanol< Hexanol< Heptanol< Octanol

-
-

• the penetration of cell membranes (made of • The increase in activity is due to the increase in lipid
solubility
protein lipid bilayer)
-
• Further increase in chain length results in rapid decrease in
• the passage of drug molecule across the

{
activity
membranes of the skin, oral cavity, bile, tissue Octanol > Nonanol
cells, kidneys, central nervous system (blood
• The decrease in activity may be because of the decreased
brain barrier) and gastrointestinal tract solubility of the compounds in extracellular fluid which
epithelium. µ
,,,,,,g,gq, ,,,gq serves as medium of transport to the cell surfaces.
µ , ,,
, ,

The dtr*g should

Oft I ←d
be soluble
in lipid for
8/26/2020 the penetration of cell membraneNew course, version 1
.
9 8/26/2020 New course, version 1 10

Solubility can be improved by: Partition coefficient

• Structural modification • Partition coefficient is a measure of the way a
compound distributes itself between two immiscible
• Salt formation mediums (aqueous and lipid).
• Use of co-solvents
• Employing surfactants
• Complexation
( X xxx
• The relative solubilities of a drug in aqueous
medium and lipids is of considerable importance in
the transport of that drug to its site of action.
• Partition coefficient can be defined as the
equilibrium constant of drug concentrations in the
two phases:

8/26/2020 New course, version 1 11 8/26/2020 New course, version 1 12

 f k¥41

• The partition coefficient (P) is a [

constant for the
>

Log P affects
r

All Pharmacokinetics Parameters depends

specified system provided that the temperature is § Solubility
on

log p
-

kept constant.
]
§ Absorption
ing -

• Partition co-efficient is T

{ "÷i÷÷÷
expressed as log value (logP) § Plasma protein binding
• Higher logP value - more lipophilicity (lipid soluble) § Metabolic clearance
• Lower logP value – more hydrophilicity (water § Volume of distribution
soluble) § Enzyme / receptor binding ¥ Ms la

§ Biliary and renal clearance

x
§ CNS penetration
• Usually partition co-efficient is determined using a
n- § Storage in tissues
octanol/water system, because they are good model § Bioavailability
for the lipid bilayer/water system in the body § Toxicity
8/26/2020 New course, version 1 13 8/26/2020 New course, version 1 14

o
• If a compound is too lipophilic (high logP value),
s
.
! #
• Conversely, if the compound is too polar (very
it will easily diffuse into lipid membranes but may
Advantage
low logP value), it will not easily diffuse into a
membrane and so could fail to reach their site
-
I Al

dis Advantage as
§ be insoluble in aqueous media (e.g. -

-
of action in effective quantities.
-gastrointestinal fluid or blood) d1ogPw%¥tfd
& issues # WE ↳ .

EW i Iad ' ! icma § t.sk EE

toys , on , j mi Hi ⇐A @→ ,
s

§ bind too strongly to plasma proteins and

if
.

b Ml GH F-
'

too lipophilic od
-

"S s
- Wibw µ too hydrophilic g
I

• According to Lipinski’s rule of five, log P should

therefore the free blood concentration will be
be less than 5 for an orally active drug.
too low to produce the desired effect ← l Ek's B

-
t ,
o
.
@s
^

%@ sm !

§ distribute into lipid bilayers and be unable to §

EM , ↳ s bs

I • Phenobarbitone, an antiepileptic drug has a

reach the inside of the cell
** " : its :*
'
.
÷: :
"
high lipid /water partition coefficient of 5.9, so
it easily crosses the blood brain barrier. l s?
of M' II
'
is
o8dIEwWliIs1ogpvaluedeibi@Nb.ss.s ←
si I l
is :* @A w I :
.

is is ! %, o

too lipophilic sbt 1

A. l W of# g. ins E
' .
s
II l
↳
Bad As ,I ←
> .Ind s .

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Ionized and unionized species: Ionization -

t€n
Constant (Ka) and Dissociation Constant (pKa)
How does of drug winaffecffheb.io#icaaetivitYofdug?
• The ionization constant (equilibrium constant), Ka for
reaction is: + -
[H3O ] [A ] ' 6
⇐ s

the structure of
drugs will behave either as an or bases Ka = ✓ →

[HA]
• A drug's acid-base
@ properties can influence -

a-

greatly its absorption and distribution * w Idiot Hsi soo

.

I Drug hydrophilic absorption f

sWIooI@lI.g Polar
=

did 4%21
absorption
.
sit
04
• The value of Ka gives a numeric value to express the
-
Io 's
Ist sich → Msbl
degree to which a compound ionizes in aqueous
←
Drug lipophilic absorption f Is 'ssis .MN
hydrophilic@g 's .

Absorption I.I # et
s
-

• Assume that a weak acidic drug , reacts with solution.

-

Wl 's ! Fu Isis
of

Ing t Absorption It -
( joint www.b.jslgsib
.

water:
g
bi ht E's
,

did A. F , ↳
-
.

Hey gift
.

M c-
+ -
-
HA + H 2O H3O +
-
A
• For example, Paracetamol is an acidic drug with a Ka of
Acid Base Conjugate acid Conjugate base 1.2 x 10-10, and is thus much less ionizes in aqueous
i w.wWlsTA@XIlbDw.Wsgti lbJ.s
us

solution than aspirin (Ka = 3.2 x 10-4).

*
Because it has an acidic and o H functional gi
,
y

; Ii @
THE Ess
. Aspirin has a higher ionization constant value
Id!
.

Isis's @
' 't
is #
app says !
←It Gls@s.sgsbt.W
Is ' Plt Ila -
his slot ,
8/26/2020 New course, version 1 is 2. Absorption
17) ' ' 8/26/2020 New course, version 1 18
SEW #3. Blog P # I 6W @g ⇐His Wl
X 's sign 's
, .
-
3 .
@QWibJIYgs.w ! - ti - ↳ wi om b 's .

• But it is difficult to deal with exponential forms, so pKa • Theoof

pKa is a measure of the strength of an acid
is used to describe the ionization of weak acid. or a base and indicate that at what extent an
• The pKa is the negative log of the equilibrium or acid-base reaction goes to completion.
ionization constant (Ka), for an acid-base reaction,
'

where water is the base. µ very important *

• A general rule for determining whether a
> pKa = - logK a chemical is strong or weak acid or base is:

I
* important '

pKa < 2 : strong acid

I
• Henderson-Hasselbalch equation relates pKa with pH of body
conjugate
ionic conf
base

- always remember
Miz @ , off im 't > ↳ D pKa 4-6 : weak acid
of drug
[A ] Id &
↳
'

Eps, i ⇐ y ↳ It > 'd w

pH = pK a + log €11 s s -
.
Al
\
-

/
1,611 bdl &
pKa 8-10 : weak base
unionized
form of
¥
[HA] PH

pKa > 12 : strong base

drug

• It is used to calculate the pH of solutions of weak acids,

xx
weak bases and buffers consisting of weak acids and
their conjugate base or weak bases and their conjugate x • The ionization of a drug is dependent on its pKa
and pH of the medium
acids.
8/26/2020 New course, version 1 19 8/26/2020 New course, version 1 20
 • The percent ionization of a drug is calculated by • Just opposite is seen when the medium is made
using the following equations if ↳ >

more acidic (lower pH) relative to the drug’s pKa

I
#
100

&
{ % ionization
for acid .
=
1 + 10
(pKa-pH)
For HA acids eg: organic acids

j ↳ .
value.
• The acidic drugs with pKa 4 to 5 will tend to be
-
{
100
% ionization =
+ -

z
For BH acids eg: protonated amines
- -

eor.ae
1 + 10
tissue or organ
(pH-pKa)
*.
I protonated 'jµ # 'T
*.
12*1
J nonionic and be absorbed significantly through
pot -d ! ski -
A -
function ←(H
.

Base

the gastric mucosa.

go
very *,

• When pH = pKa, the compound is 50% ionized (or

.

group

50% unionized).
lewd
II. ← shop ka dis A PA Hp -

• In contrast basic drugs (eg, amines, pKa 9-10)

,

W' g Q 'm iz
ft y
'

&

t
↳ ssw
if N →

Vijay is sift g

XX
• An increase of 1 pH unit from the pKa causes an HA
-

will be ionic in the acidic stomach and usually

acid (indomethacin) to become 90.9% ionized but will not be absorbed until reaching the alkaline

X
in a BH+ acid (ephedrine HCl) decreasing its percent
ionization to only 9.1%. intestinal tract (pH 8).
T -EW -

• An increase of 2 pH units shifts an HA acid to +Basic

so will
drugs
be
-

absorbed
unionized in

from the
the intestine
intestine

complete ionization (99%) and BH+ acid (0.99%).

more

+acidic
drugs will be absorbed more from stomach
8/26/2020 New course, version 1 21 8/26/2020 New course, version 1 22
.

Hydrogen Bonding (A) Intermolecular hydrogen bonding: In this type,

(
• Hydrogen bonding is the attractive force between hydrogen bonding occurs between two or more
the hydrogen atom attached to an electronegative than two molecules of the same or different
atom (N, O, S) of one molecule and an compounds.
electronegative atom of the same or a different
.÷÷÷÷÷÷.÷÷÷i÷÷÷
. "
"""""

molecule. "

÷÷÷÷: , Wj ski @

• Hydrogen bonding is classified into 2 types:

sb 's intermolecular -

- Znrolecul R o #
gb s ← Same compound

J sus

It increases the boiling and melting points of the

(B) Intramolecular hydrogen boding =
(A) Intermolecular hydrogen bonding • T
§jµ , get ; it

compounds and also their solubility in water.

-

ski
→ JIM'S a

su @ * ¥4
f

internode
-
tell @

• The molecules improve their solubility by the

formation of intermolecular hydrogen bonding
with water. SHICK It #Ht -

I I swim:# lib I@

Pharmacokineticsboss? 691, log PII

8/26/2020 New course, version 1 23 8/26/2020 New course, version 1 Proparities .

24
 (B) Intramolecular hydrogen bonding: In this type, Hydrogen bonding and biological activity

God
hydrogen bonding occurs between two atoms of
the same molecule. ÷ :*
•
structures ,

÷
. .
.
'

i
§
qq.g•g?pqoewd.esnydr.genwnding.,.,. ., .new.,.g,.a
, p.pam.ie, ?

1-Phenyl-3-methyl-5-pyrazolone shows no
÷
• It decreases the boiling and melting point of the
compound and also its solubility in water. analgesic activity. It
*:÷÷:*
is insoluble in water and
macaws
• This is because it restricts the possibility of f. only slightly soluble in ether
cookwares
• Due to intermolecular hydrogen bonding it
intermolecular hydrogen bonding with water.
forms a linear polymer resulting in large
si
*

• Thus it prevents association of the molecules,

* attractive forces, decreased solubility in non-
#

x
which would have raised the melting x point, polar solvents, so as they are not able to
boiling point.
8/26/2020 New course, version 1 25 penetrate the lipoidal tissues.
8/26/2020 New course, version 1 26

" d " re soluble insipid .

• Salicylic acid is less soluble in water, has high

→

• Whereas, 1-Phenyl-2,3-dimethyl-5-pyrazolone,
•

logis
lipid/water partition coefficient, can cross the
(Antipyrine) shows analgesic property. -

cell membrane of bacteria readily to elicit the

It is soluble in water and ether. Because -

§
action.

↳c-
Antipyrine di #§

• P-Hydroxy benzoic acid is not active as

.

Hoots
there is chance of
[
no
It bonding
inside
:g÷ggyg.gg?.ec.gtg.or*bjw..zmo1eeniee bactericidal. It forms intermolecular hydrogen

←
,

• It has weak attractive forces, soluble in non-polar - bonding, is more soluble in water and has low
solvents, so it can cross the blood brain barrier and #
-

#
partition coefficient and cannot cross the
produce activity
-
bacterial
I
membrane.
• Salicylic acid with intramolecular hydrogen bonding
d-

2nd example
H d
- i

is more active as bactericidal than p-hydroxy HOOC O HO

-

OH
benzoic acid. :÷÷÷r
1)
O H www..me intr

O
a # 'did
iambs
It # W @
intermolecular or intramolecular
O
8/26/2020 New course, version 1
it, 's #

27 8/26/2020
Intermolecular H-bonding
New course, version 1 28
OH
Tm
Isosterism and Bioisosterism
.

H
Classical isosteres
I • Isosteres are atoms or groups of atoms which have
are molecules or group of atoms which follow the

-|
the same number of electrons and electronic
electronic and steric rule of isosteres. E.www.mr @ I
steric

arrangement or at least the same number of .

valence electrons.
dl is
I, A sub
21
⇐

"" ""
"" " """" "
"

Non-classical Bioisosteres
• Isosteres possess similar physical properties. ÷
are molecules or atoms structurally distinct,
• The application of the concept of isosterism to
modify biological activity has been rise to the usually comprise different number of atoms and
,
term bioisosterism. exhibit different steric and electronic properties.
c- is'd I I, I 1 , is e, 161 I h¥

• Bioisosteres are substituents or groups with

Is
Jia of
Ig if d l i w

biological activity
s
?
Es steric

similar chemical or physical properties and

-

=
produce broadly similar biological properties to
a compound.
-

There is two type of isosterses

8/26/2020 New course, version 1 29 8/26/2020 New course, version 1 30

to
Examples Non-classical bioisosteres
CLASSICAL ISOSTERES IThey don't follow any rule of steric of
:
but they
.

→ isomer have
same biological activity
*
1) Carboxylic acid group: -COOH, -SO2NHR, -SO3H,
1) monovalent atoms or groups I
2) Hydroxyl group: -OH, -NHCOR, -NHSO2R, -CH2OH, -NHCONH2
-NH2, -F, -Cl, -CH3, -OH. @÷ # InThat
→ 1,61 .

I,
.

l is,
w

2) divalent atoms or groups

El @ WE 's
BIOISOSTERISM AND BIOLOGICAL ACTIVITY
Ist o
11
Biological activity

–CH2–, –NH–, –O–, –S– *Is

The purpose of exchanging one bioisostere for another
is to:
-

choose the monovalent

Plication
3) trivalent atoms or groups what the
classical of

Bioisosterisgm
is uses or a ?
is o Steves
of f ‫سي الفاعلية‬M −
−improve potency
T

I w I 1g I 5g
L ‫نتقائية‬R‫تعزيز ا‬
–CH=, –N=
Nth , d, CHS, OH
- - -

‫إزالة أو تقليل السمية‬

AWW d
* et, I ,

I sis
−enhance selectivity ‫ تقليل أو إعادة توجيه عملية التمثيل الغذائي‬−
4) ring equivalent ↳Ss . @ ↳ on Wl s A
.

−eliminate or reduce toxicity ‫رائك‬a‫ يزيد من الثبات ويحسن خصائص ا‬−

1
‫الدوائية‬
Benzene & thiophene −reduce or redirect metabolism
−increase stability and improve pharmacokinetic
properties
8/26/2020 New course, version 1 31 8/26/2020 New course, version 1 32
 I
①
Example: • Like –COOH, tetrazole contains an acidic proton

grpgy
%×YHc
acid

1st example .

IT
② #

1) A –COOH group is a highly polar group which can and is ionized at pH 7.4.
-

ionize and hinder absorption of any drug containing ③

• They are also planar in structure.

it. how this Problem? -
so solve
. - - can
you

,
• However, tetrazole anion is 10 times more
• Replacement of it with a bioisostere such as ÷

lipophilic than carboxylate (COO-) anion and so

tetrazole, which has similar physiochemical
F-
properties offers some advantages over the original – drug absorption is enhanced.
# Also
• Tertrazole is resistant to many of the metabolic
-
an

COOH group.

{
O N
reactions that occur on carboxylic acid (more
stable).
N
C # short note
N
O N
Explain bioisosterism with one example:
-

H
H
5-Substituetd Tetrazole Hdl @ is ¥
Carboxylic acid W 's
µ!

8/26/2020 New course, version 1 33 8/26/2020 New course, version 1 34

2nd example

2) Substitution of hydrogen with fluorine is an

example of monovalent isosteric replacement. REFERENCES
• Sterically H and F are quite similar del d l id 'm
• Graham L.Patrick, An Introduction to
.

if

• F is more electronegative than H

.. .

Medicinal Chemistry, Fourth Edition, Oxford

• If H is replaced with F it would alter the University Press, New York, 2009, 230-235
biological activity, such as the development of
• Wilson and Gisvold’s Textbook of Organic,
5- flurouracil from uracil.
Medicinal and Pharmaceutical Chemistry;
O O John H. Block, John, M. Beale, Jr.; Lippincott
Williams and Wilkins.
H F
HN HN

O N O N
H H
Uracil, a RNA base 5-Fluorouracil, an ant imetabolite
used as an anticancer agent

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