Pharmacokinetics II:

Bioavailability and Distribution

Important
In male and female slides
If you didn’t
understand any part Only in male slides
from this lecture Only in female slides
Click here!
Extra information
Objectives

● Major body fluid compartments

● Concept of compartments.
● Apparent volume of distribution (vd).
● Plasma protein binding.
● Tissue binding.
Any Future corrections will be posted
on the editing file.
make sure to check it frequently

Click Here
 Unchanged = Not metabolized
Bioavailability
Is the amount of unchanged drug that enters systemic circulation after administration and becomes available to
produce pharmacological action . Bioavailability can also be defined as the amount
of active drug in the blood
● IV provides 100% bioavailability i.e. F=1
Subcutaneous , intramuscular , oral , rectal , and other extravascular routes of administration require that the drug be
absorbed first , which can reduce bioavailability .

Bioavailability = AUC (oral) or rectal or sublingual or I.M etc.. X 100

Plasma concentration of drug

AUC( IV)

AUC = Area Under The curve

Factor affecting bioavailability :
1- factor controlling drug absorption MW, dosage forms, drug solubility, etc. ‘in lecture 1” ‘
2- First pass effect

● For Drugs administered orally Time

Bioavailability may be less than 100% for two main reasons, incomplete absorption
Note: The first pass effect affects
And first pass metabolism.
the Bioavailability by decreasing it.
Note: Generic formulation is the
actual name of a drug. Bioavailability
e.g Paracetamol

Absolute relative

-Is determined when two products are compared to

The bioavailability of a drug each other not to an intravenous standard. ● two pharmaceutical products are
after administration by any Bioequivalent when the rate and
route is compared to its - This is commonly calculated in the drug industry extent of bioavailability of active
ingredients in two product are the
intravenous standard to determine that the generic formulation is
bioequivalent to another formulation same
formulation .
Bioequivalent = Same bioavailability
-E.g tylenol(paracetamol 500 mg ) compared to ● Dosage adjustment is required
panadol(paracetamol 500 mg ) when changing formulation or
routes of administration .
Relative bioavailability Is important to get
an idea of how different formulation or
routes of administration differ in their
bioavailability .
 Distribution
Is the process by which drugs leave blood circulation and enter interstitium and/or the cells of the tissue .

● Lipid soluble drugs are distributed in the intracellular region. Because they can cross the cell membrane
● Water soluble drugs are distributed in the extracellular region.
Distribution & Apparent Volume of Distribution (Vd)
4L
Apparent Volume of Distribution (Vd) : Is the ratio of drug amount in the body
(dose) to the concentration of the drug in blood .
Explanation: 14 L
10L
dose (mg) -Drug A: (100mg dose) Has high Molecular
weight so it will stay in the plasma
Vd(L)=
Plasma concentration (mg/L) Plasma concentration Vd
Why is Vd important ? -Drug B: (100mg dose) low molecular weight
● To calculate loading dose and lipid soluble so it will go into the tissue
● Large Vd mean long duration of action .
Plasma concentration Vd

The major body fluid compartment are

28L
extracellular fluid(22%) intracellular fluid (35%)

1-Plasma (5% of body weight =4L) Fluid present inside all cells in the Note: when (Vd) is inside the plasma blood it will
2-Interstitial fluid (16%=10L) body (28L) decrease due to metabolic reactions, but (Vd) will
be high inside cells and organs.
 Multi compartment:
One compartment: Two compartments: Plasma
Plasma

Drugs may distribute through : Plasma

Intersitial fluid
Interstitial fluid

Intracellular fluid

Volume of
Compartment Drug characteristic Crossing Example Distribute in Picture
distribution

1* High molecular
CAN Not
weight 4L
cross the endothelium Trapped in blood
One 4L Heparin
2* bind with plasma
(Due to high
(Anticoagulant) (Plasma)
molecular weight)
protein

Can pass through

1* Low Molecular weight
4-14L But
endothelium to the
(14):* plasma interstitial fluid BUT 11 L Extracellular
Two 2* Hydrophilic (cannot
* Interstitial fluid pass through cellular
Can’t cross cell Atracuronium Fluid
membrane (because (muscle relaxant)
membranes)
its hydrophilic)

Equal to the
total body Diffusion to
Lipid soluble drugs will 385 L > TBW
intracellular fluid
Multi water(42) or bind strongly with tissue
(can pass through
-Digoxin
Intracellular
might be (Cardiac glycoside)
membranes because Fluid
Vd > TBW -Ethanol (34-41)=TBW
higher its lipid soluble)
 Volume of distribution (Vd)

The characteristics are usually opposites

Low Vd High Vd
Low is Molecular weight
-Free drugs ( not bounded to plasma proteins

distributed in extracellular compartments Have higher concentrations in

(plasma & interstitial fluid). tissues than in plasma.

Polar comp or lipid insoluble drugs.

E.g. gentamicin, atracurium Lipid soluble

High MW (molecular weight ) e.g. heparin.insulin Distributed intracellularly

High plasma protein binding e.g. warfarin (anticoagulant) For example: digoxin, phenytoin, morphine

Do not cross BBB ( blood brain barrier ) or placental

barriers.
Note: Drugs that cross the blood brain barrier, will cross
placental barrier and vice versa.
 The greater the blood flow to tissues, the more distribution that occurs from plasma
to interstitial fluids.
Cardiac output and
blood flow
Drugs distribute more rapidly to brain,
liver & kidney > more than skeletal muscles & fat.

Most lipid soluble drugs (unionized, uncharged,

nonpolar) cross biological membranes
Physical and chemical ● molecular weight
properties of the drug PKa
Factors
●
affecting Hydrophilic drugs (Ionized, Charged, Polar) go through ● Lipid solubility
distribution slit junctions in endothelial cells of capillaries

*Blood brain barrier (BBB):

Brain has tight junction called Blood Brain Barrier
-Only lipid soluble drugs or actively transported drugs can cross BBB.
-Hydrophilic drugs (ionized or polar drugs) can not cross BBB.
Endothelial cells of capillaries in tissues other than -Inflammation as in meningitis increase permeability to hydrophilic drugs
brain have wide slit junctions allowing easy movement, e.g. penicillin & gentamysin
Capillary permeability
permeation and distribution.
*Placental barrier
Lipid soluble drugs can cross placental barrier
and enter the fetal blood.
Slit junctions are
seen in this pic No slit junctions.
The molecule has to diffuse
through the membrane (has
to be hydrophobic) or it has to
be transported through
carriers

● Extensive & strong plasma protein binding

Has affinity for acidic drugs as warfarin,
Albumin will cause more drug to stay in the blood
phenytoin, aspirin.
compartment.Therefore,they tend to have lower
Plasma protein distribution (Vd).
binding ● In blood, drugs exist in two forms bound and
unbound forms in equilibrium Bound drugs become
free when the unbound drugs run out (so it’s as if they are
(VD‫)ﻋﻛﺳﯾﺔ ﻣﻊ‬ Alpha 1- acid Has affinity for basic drugs (cationic) as
stored while bound to proteins and they come out when
Factors glycoprotein diazepam, quinidine. there is a demand)
affecting
distribution Unbound drug (free) bound drug

Tissue binding ● Drugs can bind to specific tissues and will have high volume of distribution (Vd).
(because the plasma concentration will be low therefor Vd will be high)
( VD ‫)طردﯾﺔ ﻣﻊ‬ E.g. Tetracycline binds to bone
 Opposites
Bound form of drug Unbound form of
drug

non diffusible diffusible

can't cross endothelial cross endothelial barrier

barrier

can't combine with combine with receptors

receptors

inactive active

not available for available for metabolism

metabolism & excretion & excretion

has long duration of has short duration of

action (t ½). action (t ½).
 Characters & consequences of Binding Displacement

- Usually reversible. Competition between two drugs for the same binding
site on the plasma proteins may cause → displacement
of one drug & increasing its concentrations & effects.
- determines volume of distribution (vd).
e.g.
- Slows drug metabolism & excretion. Aspirin + Albumin-warfarin →Albumin-aspirin + free
warfarin → bleeding.
- Prolongs duration of drug action (t1/2).
Explanation: Replacement of warfarin by aspirin Will cause an
- Result in clinically important drug interactions. abundance of free warfarin ( anticoagulant ) in the blood
circulation and that will lead to bleeding

Extra info: The reason for displacement is the difference in protein affinity
to drugs. The affinity of albumin to aspirin is higher than the affinity of
albumin and warfarin. That's why when aspirin is freely present in the
circulation. It throws warfarin out of albumin and binds to it instead
MCQ MQ team439 made awesome review questions
Check them out here!

1) Lipid soluble drugs are distributed in

A) Extracellular region. B) Intracellular region. C) Plasma D) Interstitial fluid

2) Drugs distribute more rapidly to…

A) Skeletal muscles B) Connective tissues. C) Brain. D) Stomach.

3) An unbound form of drug is... ANSWERS

1 B-
A) Diffusible. B) Inactive. C) Non Diffusible. D) Has long t(½)
2 C-

4) If a root of administration has 100% Bioavailability. F would be... 3 A-

A) F>1 B) F <1 C) F = 100 D) F = 1 4 D-

SAQ
1) Drug exists in blood in two forms, what are they?

2) Name 3 factors affecting distribution.

3) In what compartment do lipid soluble drugs get absorbed in?

4) What are the characters of an unbound form of drug?

ANSWERS
A1) Bound & unbound.
A2) Capillary permeability, plasma protein binding & tissue binding.
A3 In the intracellular compartment.
A4) Diffusible, active, can cross endothelial barrier, has short (t1/2)
 ‫‪Girls team members‬‬ ‫‪Team leaders‬‬

‫‪GOOD‬‬ ‫ﻣﻧﯾرة اﻟﺳدﺣﺎن‬ ‫طرﻓﺔ اﻟﺷرﯾدي‬

‫ﺣﻣود اﻟﻘﺎﺿب‬
‫●‬
‫●‬

‫!‪LUCK‬‬
‫ﻟﯾﻧﺎ اﻟﻣزﯾد‬
‫ﺳﺎرة اﻟﻘﺣطﺎﻧﻲ‬
‫ﻧورة اﻟﻣﺳﻌد‬ ‫‪Boys team members‬‬
‫وﺳﺎم ال ﺣوﯾس‬
‫راﻧﯾﺎ اﻟﻣطﯾري‬
‫ﻋﺑداﻟﻠطﯾف اﻟﻣﺷﺎط‬
‫‪this lecture was done by :‬‬ ‫ﻧورة اﻟدﺧﯾل‬
‫اﺣﻣد اﻟﺣواﻣدة‬
‫اﺳﯾل اﻟﺷﮭري‬
‫ﺑﺳﺎم اﻻﺳﻣري‬
‫‪Contact us:‬‬ ‫اﻟﺟوھرة اﻟﺑﻧﯾﺎن‬
‫ﻣﺎﺟد اﻟﻌﺳﻛر‬
‫ﺷﺎدن اﻟﻌﺑﯾد‬
‫‪[email protected]‬‬ ‫ﺑﺎﺳل ﻓﻘﯾﮭﺎ‬
‫ﺳدﯾم آل زاﯾد‬
‫ﻋﺑداﻟرﺣﻣن اﻟدوﯾش‬
‫‪@pharmacology439‬‬ ‫روان ﺑﺎﻗﺎدر‬
‫ﺣﻣد اﻟﻣوﺳﻰ‬
‫ﻣﯾس اﻟﻌﺟﻣﻲ‬
‫راﻛﺎن اﻟدوھﺎن‬
‫ﻧورة اﻟﺳﺎﻟم‬
‫ﻓﯾﺻل اﻟﻌﺗﯾﺑﻲ‬
‫ﻧوف اﻟﺳﺑﯾﻌﻲ‬
‫ﻣﺣﻣد اﻟﻘﮭﯾدان‬
‫ﻧدى ﺑﺎﺑﻠﻠﻲ‬
‫ﯾزﯾد اﻟﻘﺣطﺎﻧﻲ‬
‫داﻧﺔ ﻧﺎﺋب اﻟﺣرم‬