ADME

And

PHARMACOKINETICS

ADME lecture 1Contents ...

• What are ADME and Pharmacokinetics?• Absorption• Distribution

Part 1

What are ADME and pharmacokinetics?

PHARMACOKINETICS

“Drug movement” (Greek)

Mathematical description of the

various processes that constitute

ADME.

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.

DistributionThe 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 …

EliminationThe 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.

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

LipidWater Water

DRUG

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 Inefficient Hydrocarbons Anaesthetics Alcohols Lipids Most drugs

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

Blood

Kidneys

etc

Liver

Fat

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

Total drug concentration in blood greater than in cell.

Lipid

Intra-cellular bindingBLOOD CELL

Drug Drug

Drug.Protein Lipid Nucleic acid

Total drug concentration in blood lower than in cell.

Lipid

Overall binding

Balance depends upon relative binding affinity in blood and tissues.

Drug.Protein Lipid Nucleic acid

BLOOD CELL

Drug Drug

Drug.ProteinLipid

Terms with which you should be familiar ...

ADME PharmacokineticsAbsorption Passive diffusionDistribution Faciliated diffusionMetabolism Active transportExcretionElimination

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