PPFB 1 - INTRO TO ADMET

a drugs journey through the body,processes and factors that affect ADMET and influence of ADMET on drug discovery

What is ADMET ?

Absorption

Distribution

Metabolism

Elimination/Excretion

Toxicity

note : refers to the different phases of life of the drug which are critical for drug development

What is absorption ?

• Passage of the drug from the site of administration into the plasma.

• Important for all routes except the intravenous route.

What are some main administration routes?

• oral, sublingual, rectal, transdermal ( application to epithelial surfaces, inhalation

Injection

• (subcutaneous, intramuscular and intrathecal - spinal cord )

Key model for absorption ?

• The drug that is best absorbed is in a solution

How do particle size and formulation effects absorption?

• Smaller particle size increases surface area,increased absorption

• suspension is not soluble; it needs to be turned into a solution

• faster it is turned into a solution = faster absorption

How does food affect the absorption rate ?

• It considers gut content and splanchnic blood flow

• different drugs act differently, when taken with food longer in the stomach = not an immediate effect

• Depends on gastrointestinal motility = How the GI empties

How do Physicochemical factors affect the rate of absorption?

• when the concentration gradient drives diffusion

• Drug absorption through epithelial barriers by

  passive transfer (diffusion) occur a rate

  determined by the ionisation and lipid solubility of

  the drug molecules.

Ionisation

• uncharged,better absorption across the membrane

What is the first pass effect in the oral routes ?

After absorption, it can go to 2 places

1. gut wall and hepatic metabolism( liver) , eliminated - FIRST PASS

2. intact drug in systemic circulation, pharmacological effect

What is distribution ?

• Drug distribution is the process by which the drug reversibly leaves the blood streams to other parts of the body and into the tissues

What is volume distribution (Vd)?

• The fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma (Cp).

What is the single vs 2-compartment model?

2 models apply - see distribution

• one compartment model - homogeneously distributed at the same time

• 2-compartment model - the drug enters the blood vessels, then starts to distribute to the rest of the body

Drugs can enter and leave the peripheral compartment via the central compartment:

Vd= Vi + Vt

What are Key factors ?

• Blood Flow

• Capillary permeability

• Binding of the drug to plasma and tissue proteins - highly bound to albumin, decreases the volume of distribution

• Lipophilicity and partitioning into body fat

What is a Metabolism ?

• Metabolism facilitates the elimination process

• It tries to modify, change drugs that aren’t easily excreted by adding groups etc

What are some examples of drugs that affect metabolism

These are metabolised by CYP450 isoenzymes.

What are drug interactions due to hepatic metabolism?

• Nearly always due to interaction at Phase I enzymes, rather than Phase II

• Some metabolising enzymes are genetically altered in some individuals

What is the relationship,link between drug and metabolite?

What is drug clearance beyond CYP450?

Phase I reaction not involving CYP450 systems:

• Amine oxidation (catecholamine or histamine)

• Alcohol dehydrogenation (ethanol)

• Esterase (Aspirin metabolism in the liver)

• Hydrolysis (procaine)

What are the 2 main routes of Elimination?

The two main routes of elimination are:

1. biliary ( in bile ) excretion and enterohepatic circulation

2. renal clearance

CL total = Clm ( hepatic ) + Clr ( renal )

The rate at which a drug is eliminated from the body influences its duration of action and potential accumulation, affecting toxicity levels

Describe renal clearance

Process/flowchart - drug safety

What can cause toxicity ?

• Hepatic dysfunction impairs drug metabolism, exacerbating the potential for toxic effects.

• Kidney failure reduces the elimination of drugs that are primarily excreted through the kidneys, leading to drug accumulation and increased risk of toxicity.

What is the therapeutic index/range ?

• balance between safe and toxic

What is considered when making a decision?

ADMET and Pharmacist decision point

• Route selection (absorption)

• Food advice (absorption)

• Dose adjustment

(metabolism/elimination)

• Monitoring need (toxicity)

ADMET Knowledge alone is not enough

• ADME tells us what can happen

• PK tells us how much and when