ADME 1

Absorption and Distribution

 Phases of drug action
Three phases:

1. Pharmaceutical phase:
disintegration, release, dissolution

2. Pharmacokinetic phase:
absorption from GI tract into blood supply, metabolism

3. Pharmacodynamic phase:
interaction of drug with target, effect
 Reasons for failure in clinical trials

Kola, I., & Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3(8), 711–715.
 What is pharmacokinetics?

• Pharmacokinetics: what does the body do to

the drug?
• The study of the movement of drugs in the
body
• Absorption
• Distribution
• Metabolism (biotransformation)
• Excretion
 Absorption
• It is the process of entry of drug from site of
administration into systemic circulation.
• Absorption involves transportation of the drug across
biological membranes
• Different mechanisms for a drug to be transported
across a biological membrane:
• Passive (simple) diffusion
• Active transport
• Facilitated diffusion
• Pinocytosis
 Simple (passive) diffusion
• The major means for transportation of drugs across
cell membranes
• The substances move across a membrane according
to a concentration gradient
• The concentration gradient is the factor that
determines the route and rate of the diffusion
• No energy is required
 Simple (passive) diffusion
• The concentration gradient and the lipid
solubility of the drug are the two main factors
that determine the diffusion rate of the drug.
• Molecular weight of highly lipophilic drugs is not
important BUT MW OVER 1000 is generally
restrictive
• Simple diffusion of drugs with high solubility in
water occurs via aqueous pores found on the cell
membrane (e.g. caffeine, ascorbic acid,
acetylsalicylic acid).
• Aqueous pores do not play a major role in the
simple diffusion of lipophilic drugs across the cell
membrane.
 Active transport
• The transportation of the drug molecules across the
cell membrane against a concentration or an
electrochemical gradient
• It requires energy (ATP) and a special transporter
(carrier) protein.
• There is a transport maximum for the substance (the
rate of active transport depends on the drug
concentration in the environment).
• Saturable
 Facilitated diffusion

• Occurs by the carrier proteins.

• Net flux of drug molecules is from the high
concentration to low concentration.
• No energy is required.
• Saturable.
 Comparison
Mechanism Direction Energy required Carrier Saturable
Passive diffusion Along gradient No No No
Facilitated diffusion Along gradient No Yes Yes
Active transport Against gradient Yes Yes Yes
 Pinocytosis

• Drugs which have MW over 900

can be transported by
pinocytosis.
• It requires energy.
• The drug molecule inserted into
the cell within small vesicles.
Factors affecting drug absorption
A) DRUG-RELATED FACTORS
• Molecular size
• Lipid solubility
• Degree of ionization
• Stability

B) SITE of APPLICATION RELATED FACTORS

• Blood flow (at site of application)
• Area of absorption
 Routes of Administration
Two main pathways (routes)

Local Systemic
administration administration

• Different drugs are administered via different routes

• A number of factors are involved in choosing best route for a
particular drug. The method chosen depends upon the target
organ and the pharmacokinetics of the drug
• The main routes are oral, sublingual, rectal, topical, epithelial,
inhalation and injections.
• Absorption is faster from i.v. > inhaled > i.m. > oral > dermal
administration
 Local Administration
• If the desired drug action site (target tissue) is on the
surface of the body or if the site can be reached easily, i.e.
by a needle, drugs can be applied locally.
✓ Epidermal (percutaneous)
✓ Intracutaneous
✓ Conjunctival
✓ Intranasal
✓ Buccal
✓ Intrathecal
✓ Intrapleural
✓ Intrauterine
✓ Intracardiac
✓ Intravaginal
✓ Intraarticular
 Local Administration
• Epidermal (percutaneous):
✓ Application of some drugs over the surface of the skin in
some dosage forms like, creams, lotions or solutions.
✓ There are some factors that affect the absorption of an
epidermal administered drug:
a) Damage in the stratum corneum layer
b) Region of the body
c) High lipid-water partition coefficient and small
molecular size
d) Cleansing of the skin and friction
 Local Administration
• Intracutaneous:
✓ Generally used for allergic or bacteriological tests or
application of local anesthetics.
✓ Volume over 0.1 ml is not generally desired in this kind of
application.
 Local Administration
• Conjunctival:
✓ Ophthalmic solutions or
ophthalmic ointments are
applied locally for some eye
or eyelid diseases.
• Intranasal:
✓ Nasal sprays or solutions can
be used for nasal mucosa or
paranasal sinus diseases (i.e.
allergic rhinitis in spring).
 Local Administration

• Intrathecal:
• Some local anesthetics, analgesics or antibiotics are injected
into the spine
 Systemic administration
• If a widespread effect throughout the body is desired or
if you can’t reach the target tissue to obtain a local
effect, then systemic routes are used.

• There are 4 main routes for systemic administration:

➢Enteral route
➢Parenteral route
➢Inhalation
➢Transdermal route
 Enteral route
• Drug goes to GI tract and is absorbed from GI tract.
• Via 3 dosing routes:
✓Oral
✓Sublingual
✓Rectal
 Oral route
• This is the most often used route
• This route is known to be the safest, easiest and the most
economical way of administering drugs.
• Drug molecules are mostly absorbed from duodenum, jejunum
and upper ileum.
• Drugs disintegrate and dissolve before the absorption process.
 Oral route
• Advantages:
– convenient: can be self-administered, pain-free, easy to take
– absorption: takes place along the entire GI tract
– cheap: compared to parenteral routes

• Disadvantages:
– sometimes inefficient: only part of the drug may be absorbed
– 1st pass effect: drugs absorbed orally are initially transported to the liver
via the portal vein
– irritation to gastric mucosa → nausea and vomiting
– destruction of drugs by gastric acid and digestive juices
– effect too slow for emergencies
– unpleasant taste of some drugs
– unable to use in an unconscious patient (patient compliance is a problem)
 Other enteral routes
Sublingual Route
• Especially high lipophilic drugs are used by this route.
• pKa is the major rate limiting factor - saliva pH is 7.0
• Cardiac nitrates, Ca+ channel blockers like nifedipine and some steroid sex hormone
pills can be used by this route.
• Advantages:
✓ The effect starts very quickly.
✓ Systemic bioavailability of the drug is generally very high (no first pass
metabolism).
• Disadvantages: inconvenient, small doses, unpleasant taste of some drugs

Rectal route
• Enema: as a liquid drug formulation
• Rectal suppositories: as a solid drug formulation.
• There is no first-pass metabolism in this route and the effect starts immediately.
• good for drugs affecting the bowel (laxatives)
• useful for unconscious or vomiting patients or uncooperative patients (children)
 1st Pass Effect
• drug is absorbed from the gut and delivered to the liver by the portal circulation
• enzymes in the liver metabolize the drug to an inactive species before it reaches
the systemic circulation
– inactive product = metabolite that does not possess the desired
pharmacological activity
• the greater the 1st pass effect:
– the less the drug will reach the systemic circulation when administered
orally
 Bioavailability
• The “fraction of unchanged drug that reaches to the systemic
circulation from the administration site (after passing
through the liver)”.
 Bioavailability
Plasma concentration
70

60

i.v. route
50 (AUC)o / (AUC)iv
40

30
oral route

20

Time (hours)
10

0
0 1 2 3 4 5 6 7 8 9
 Factors affecting bioavailability
Drug Related Factors That Affect Bioavailability:
➢ Particle size
➢ Crystalloid structure
➢ Salt compound / free
➢ Drug formulation affects the dissolution and disintegration.
Solutions>Suspensions>Capsule>Tablet>Coated tablet>Sustained Release (SR) tablets

Patient Related Factors That Affect Bioavailability:

➢ Differences in first-pass metabolism
➢ drug metabolism differences between individuals
➢ diseases that affect the GI motility
➢ age
➢ gender
➢ body weight
➢ drug-drug or drug-food interactions
 Lipinski’s rule of five
Good oral absorption and permeation if:

• Molecular weight ≤ 500 Da

• H-bond acceptors ≤ 10
• H-bond donors ≤ 5
• clogP ≤ 5

Exceptions: drugs that can be transported by carrier proteins

Lipinski, C.A., Lombardo, F., Donimy, B.W., & Feeny, P.J. (1997). Advanced Drug Delivery Reviews,
23, 3-25
 25 Molecular weight

20

15
Plot of frequency of
frequency %

occurrence against molecular

weight for 594 marketed oral
10 drugs

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0-15 0-20 0-25 0-30 0-35 0-40 0-45 0-50 0-55 0-60 0-65 0-70 0-75 0-80 0-85 0-90 0-95 -100
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95
0

Molecular Weight

Most oral drugs have molecular weight < 500

 Veber rules
After examination of oral bioavailability of
potential drug candidates in rats, Veber
concluded that the number of rotatable bonds
was important for absorption.

For good oral absorption:

Number of rotatable bonds < 10
Polar surface area < 140 Å2

Veber et al, J. Med. Chem. 2002, 45, 2615.

 Number of rotatable bonds
A rotatable bond is defined as any single non-ring bond,
attached to a non-terminal, non-hydrogen atom. Amide C-N
bonds are not counted because of their high barrier to rotation.
No. of rotatable Bioavailability
OH
O
H
N bonds
O
Atenolol 8 50%
H2N

OH
H
O N
Propranolol 6 90%

The number of rotatable bonds influences, in particular,

bioavailability and binding potency. Why should this be so?
 Question
Do you think doxorubicin is orally bioavailable?

MW = 543 g/mol

Doxorubicin
 Parenteral route
• 3 Routes via injection:
▪ Into veins or arteries (IV)
▪ Intramuscular (IM)
▪ Subcutaneous (SC)
• Following IV injection, the effect starts immediately and the
bioavailability is 100%.
• IV Bypasses all barriers to absorption
• IM injection is generally applied to gluteal and deltoid muscles
• SC bypasses epidermis - only barrier is dermis
• Usually for drugs with poor oral bioavailability and very polar
drugs
 Inhalation
• For drugs with small particle size and high lipid-water partition coefficient.
 Transdermal
• Transdermal therapeutic systems (TTS, patch) are
used for transdermal drug application
• These are absorbed from the skin to systemic
circulation
• These are generally lipophilic drugs
 Distribution
Distribution: Movement of drug from the central
compartment (blood) to peripheral compartments
(tissues) where the drug is present.
There is a reversible transfer of a drug to and from the
systemic circulation
Absorption Distribution
BLOOD TISSUES

The major body compartments are:

Intracellular
—plasma (5% of body weight) Cell membrane
compartment

—interstitial fluid (16%) Interstitial compartment

—intracellular fluid (35%) Endothelium of capillary wall Extracellular

—transcellular fluid (2%) Intravascular (Plasma)

compartment
—fat (20%)
Body water
Factors Affecting the Distribution of Drugs

• Diffusion Rate
• The Affinity of the Drug to the Tissue Components
• Blood Flow (Perfusion Rate)
• Binding to Plasma Proteins
 Factors Affecting the Distribution of Drugs
• Diffusion Rate:
✓ There is a positive correlation between the diffusion rate of the
drug and the distribution rate
• The Affinity of the Drug to the Tissue Components:
✓ Some drugs tend to be concentrated in particular tissues (eg.
iodine in thyroid gland)
• Blood Flow (Perfusion Rate):
✓ There is a positive correlation between the blood flow in the
tissue and the distribution of the drugs.
✓ Kidney, liver, brain and heart have a high perfusion rate (ml/100
g tissue/min) in which the drugs distribute higher;
✓ Skin, resting skeletal muscle and bone have a low perfusion rate.
✓ The total concentration of a drug increases faster in well-
perfused organs.
Factors Affecting the Distribution of Drugs

• Binding to Plasma Proteins:

✓ The most important protein that binds the drugs in
blood is albumin for most drugs
✓ Acidic drugs (salicylates, vitamin C, sulfonamides,
barbiturates, penicillin, tetracyclines, warfarin,
probenecid etc.) are bound to albumin.
✓ Basic drugs (streptomycin, chloramphenicol, digitoxin,
coumarin etc.) are bound to alpha-1 and alpha-2 acid
glycoproteins, globulins, and alpha and beta
lipoproteins.
Properties of plasma protein-drug binding
• Saturable:
One plasma protein can bind a limited number of drug
molecules
• Non-selective:
More than one kind of drug (different chemical
structures or pharmacological effects) can be bound to
the plasma protein
• Reversible:
The bonds between the drug and plasma protein are
weak bonds (non-covalent)

Bound fraction Unbound fraction

 PropertiesDrug storage
of plasma protein-drug binding
• Only the free (unbound) fraction of the drug circulating in
plasma can pass across the capillary membrane .
• Bound fraction serves as “drug storage”
• Stored drug molecules in tissues serve as drug reservoir.
• The duration of the drug effect may get longer.
• May cause a late start in the therapeutic effect or a decrease
in the amount of the drug effect..

[DRUG]=1 mM [DRUG]=1 mM

[DRUG+PROTEIN]=9 mM

[TOTAL DRUG]=10 mM [TOTAL DRUG]=1 mM

PLASMA INTRACELLULAR FLUID

 Distribution to the CNS
• A blood-brain barrier exists (except some areas in the brain) which limits
the passage of substances.
• Non-ionized, highly lipophilic, small molecules can pass into the CNS and
show their effects.
• Some antibiotics like penicillin can pass through the inflamed blood-brain
barrier while it can’t pass through the healthy one.
 Volume of distribution
The apparent volume of distribution, Vd, is defined as the
volume of fluid required to contain the total amount of drug in
the body at the same concentration as that present in the
plasma.

Volume of Distribution = Amount of drug administered

(dose) (mg) / concentration of drug in plasma (mg/ml)
• Volume of Distribution (Vd) = Dose / C0’
• Most of the times, volume of distribution calculated in this
way is not equal to the real total volume of physiological
liquid compartments in which the drug is distributed.
• It is really an “apparent volume of distribution (Vd)”.
 Volume of distribution
• Small volume indicates extensive plasma protein binding, but
large volume indicates extensive tissue binding.
• Vd is increased by increased tissue binding, decreased plasma
binding and increased lipid solubility.
• N.B. in average 70 kg adult, the total body water is approx. 42
liter, extracellular volume is 12-14 liter and plasma volume is 4
liter, so:
✓Drugs concentrated in plasma have Vd 3-4 L e.g. heparin.
✓Drugs distributed extracellularly have Vd 12-14 L e.g. aspirin.
✓Drugs distributed to all body fluids have Vd 42 L e.g. phenytoin
and alcohol.
✓Drugs distributed intracellularly e.g. digoxin has Vd 500 L,
imipramine 1600 L.