Transcript Dr. Phil Rowe Reader in Pharmaceutical Computing

ADME
Dr Phil Rowe
School of Pharmacy & Chemistry
John Moores University
Liverpool
ADME lecture 1
Contents ...
• What are ADME and
Pharmacokinetics?
• Absorption
• Distribution
Part 1
What are ADME and
pharmacokinetics?
ADME
Absorption
 Distribution
 Metabolism
 Excretion

Elimination
Absorption
The movement of drugs into the body
Do not consider a drug to be fully absorbed
until it reaches the blood stream. Drugs
administered orally, intramuscularly,
subcutaneously etc need to undergo
absorption (unless effect is to be topical).
Only i.v. route does not require absorption.
Distribution
The movement of drugs around the body
Once absorbed, drugs will generally
move around the body. A drug
molecule may spend some time in one
organ, then be carried by the blood to
another organ and so on …
Elimination
The removal of drugs from the body
Elimination is the final removal of the drug from
the body. This is subdivided into…
• Metabolism: Destruction of the drug by
chemical alteration.
• Excretion: Removal of the drug from the body
(Generally in the urine). Note that the term
‘Excretion’ is only used if the drug is removed
chemically unaltered.
PHARMACOKINETICS
“Drug movement” (Greek)
Mathematical description of the
various processes that constitute
ADME.
Part 2
Absorption
Absorption
Three mechanisms by which
drugs may cross membranes:
Passive diffusion
 Facilitated diffusion
 Active transport

Passive diffusion MUCH more common than
any of the others.
Passive diffusion
Water
DRUG
Lipid
Water
Requirements for
passive diffusion
Water solubility
 Lipid solubility

* Almost all drugs are sufficiently water soluble
to undergo passive diffusion, but some do lack
the necessary lipid solubility.
* In practice, passive diffusion depends mainly
on lipid solubility.
Specificity of passive
diffusion
Non-specific. No requirements as to the
size or shape of the molecule, just so long
as it is lipid soluble.
Efficiency of passive
diffusion
Efficient
Hydrocarbons
Anaesthetics
Alcohols
Lipids
Most drugs
Inefficient
Carbohydrates
Proteins
Ionised molecules
Facilitated diffusion
and active transport
• Both operate via a transport protein that carries a
molecule across a membrane.
• Active transport is energy requiring, but facilitated
diffusion is not.
• The transport proteins will only carry structurally
specific groups of molecules e.g. amino acids
• Very few drugs have structures sufficiently similar
to any naturally occurring group of molecules that
have a carrier protein. Therefore rarely arises.
Part 3
Distribution
Distribution
Kidneys
Fat
Blood
Liver
etc
Factors influencing
distribution of a drug:
 Ability
to undergo passive
diffusion (Already described)
 Binding to macromolecules
Plasma protein binding
BLOOD
CELL
Drug
Drug
Drug.Protein
Lipid
Total drug concentration in blood greater than in cell.
Intra-cellular binding
BLOOD
CELL
Drug
Drug
Lipid
Drug.Protein
Lipid
Nucleic acid
Total drug concentration in blood lower than in cell.
Overall binding
BLOOD
CELL
Drug
Drug
Drug.Protein
Lipid
Drug.Protein
Lipid
Nucleic acid
Balance depends upon relative binding
affinity in blood and tissues.
Terms with which you
should be familiar ...
ADME
Absorption
Distribution
Metabolism
Excretion
Elimination
Pharmacokinetics
Passive diffusion
Faciliated diffusion
Active transport
What you should be
able to do
 Distinguish
between metabolism and excretion
 Describe the mechanism of passive diffusion
 Predict whether a given molecule will easily
undergo passive diffusion
 Identify the factors that may influence the
distribution of a given drug