Tuesday Lecture

8/2/2019 Tuesday Lecture

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ADME

The in vivo hurdle continues



2) In Vivo Preclinical Studies

• Carried out in Rodents (rats)



A Absorption

D Distribution

M Metabolism

E Elimination



• Absorption - how the drug is taken into the body.

• Distribution

- how the drug is moved and into which tissues.

• Metabolism

- how the drug is changed by the body

• Elimination

- how the drug is removed from the body.



Distribution

How is a drug distributed throughout the body?



The Circulation



Blood Flow

• Distribution depends on blood flow, solubility in blood

Venous Arterial



Distribution

• A drug is quickly distributed to organs with

a large supply of blood:

heart, liver, kidneys.

• A drug is more slowly distributed to/from

other internal organs/tissues:

skin, fat, and muscle.



•Plasma protein binding

•Storage sites

•Volume of distribution

•Physical Barriers

Barriers to Drug distribution




Protein-binding (serum)

•only free drugs, not bound drugs, produce

a

therapeutic effect.



Storage sites

•subcutaneous deposition (slow release)

•affinity for lipoid (fat) or aqueous tissue




Volume of distribution

•grams of drug/kg body mass

•grams of drug/L of volume




•Physical Barriers





• Physical Barriers

Blood-brain barrierPlacental barrier

Testicular barrier




• Blood-brain barrier

X

BrainBlood



• Blood-brain barrier


Regular capillary wall

Protected capillary wall



Distribution

• Lipid-soluble drugs easily cross through cellmembranes while water-soluble drugs

cannot.

• Lipid-soluble drugs of the right size andcharge can also cross through blood-brainbarrier.



• Absorption - how the drug is taken into the body.

• Distribution

- how the drug is moved and into which tissues.

• Metabolism


• Elimination

- how the drug is removed from the body.



• Metabolism




Metabolism

• Biotransformation - the body’s ability to

change a drug into a form that can then be

excreted.



Metabolism

• Majority of drugs are metabolised in the liver.

• Some drugs are metabolised in the plasma,

kidneys, or intestines.

• Affected by: liver disease, heart failure,

genetics, environment, and developmental

changes (puberty, aging etc).



Chemical Processes of Metabolism

OxidationReductionHydrolysis

Conjugation

• Metabolites can be Active / Inactive / Toxic



Metabolism

• 90% metabolised by liver into acetaldehyde

• 10% unmodified from urine, lungs (exhaled)



Side Effects of Metabolites

• Metabolised by liver into formaldehyde

• Methanol Poisoning causes 20% blindness

• Can be treated with ethanol



Using Metabolism in Drug Design

Prodrugs



Prodrugs

•Improve membrane permeability - esterification

COOCH3 COOH



Prodrugs

Salicylic Acid

gastric bleeding

Aspirin

• Mask drug toxicity and side effects



• Prolong drug activity

Slow release of esterified drug (lipid) into blood

Prodrugs

COOCH3 COOH

Storage e.g fat tissue Blood



•Targeting of drug

Prodrugs

pH 5

urineCH2OFormaldehyde antibacterial

Bladder



•Improve water solubility

•Increase chemical stability•See previous lectures

(hypoxia, antibodies etc)

Prodrugs





Determining the Therapeutic Range

of a drug



Therapeutic Range

Toxic Range

Margin of safety

Therapeutic Range

Time

BloodConcentration



Dosing in the Therapeutic Range









Therapeutic Range

• Use ADME and Dosing Studies and FormulationMethods

Documents

Tuesday Lecture