tuesday lecture
TRANSCRIPT
8/2/2019 Tuesday Lecture
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ADME
The in vivo hurdle continues
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2) In Vivo Preclinical Studies
• Carried out in Rodents (rats)
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A Absorption
D Distribution
M Metabolism
E Elimination
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• 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.
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Distribution
How is a drug distributed throughout the body?
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The Circulation
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Blood Flow
• Distribution depends on blood flow, solubility in blood
Venous Arterial
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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.
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•Plasma protein binding
•Storage sites
•Volume of distribution
•Physical Barriers
Barriers to Drug distribution
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Barriers to Drug distribution
Protein-binding (serum)
•only free drugs, not bound drugs, produce
a
therapeutic effect.
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Storage sites
•subcutaneous deposition (slow release)
•affinity for lipoid (fat) or aqueous tissue
Barriers to Drug distribution
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Volume of distribution
•grams of drug/kg body mass
•grams of drug/L of volume
Barriers to Drug distribution
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•Physical Barriers
Barriers to Drug distribution
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Barriers to Drug distribution
• Physical Barriers
Blood-brain barrierPlacental barrier
Testicular barrier
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Barriers to Drug distribution
• Blood-brain barrier
X
BrainBlood
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• Blood-brain barrier
Barriers to Drug distribution
Regular capillary wall
Protected capillary wall
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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.
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• 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.
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• Metabolism
- how the drug is changed by the body
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Metabolism
• Biotransformation - the body’s ability to
change a drug into a form that can then be
excreted.
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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).
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Chemical Processes of Metabolism
OxidationReductionHydrolysis
Conjugation
• Metabolites can be Active / Inactive / Toxic
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Metabolism
• 90% metabolised by liver into acetaldehyde
• 10% unmodified from urine, lungs (exhaled)
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Side Effects of Metabolites
• Metabolised by liver into formaldehyde
• Methanol Poisoning causes 20% blindness
• Can be treated with ethanol
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Using Metabolism in Drug Design
Prodrugs
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Prodrugs
•Improve membrane permeability - esterification
COOCH3 COOH
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Prodrugs
Salicylic Acid
gastric bleeding
Aspirin
• Mask drug toxicity and side effects
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• Prolong drug activity
Slow release of esterified drug (lipid) into blood
Prodrugs
COOCH3 COOH
Storage e.g fat tissue Blood
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•Targeting of drug
Prodrugs
pH 5
urineCH2OFormaldehyde antibacterial
Bladder
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•Improve water solubility
•Increase chemical stability•See previous lectures
(hypoxia, antibodies etc)
Prodrugs
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Determining the Therapeutic Range
of a drug
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Therapeutic Range
Toxic Range
Margin of safety
Therapeutic Range
Time
BloodConcentration
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Dosing in the Therapeutic Range
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Dosing in the Therapeutic Range
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Dosing in the Therapeutic Range
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Therapeutic Range
• Use ADME and Dosing Studies and FormulationMethods