Drug metabolism and excretion

Question 1

In terms of elimination, what are drug metabolism and excretion?

Answer 1

• Metabolism
Removal of lipid-soluble drug molecules to prevent reabsorption by kidneys
Achieved by converting drugs into water-soluble molecules
Mostly in the liver, but also in plasma, lung and intestinal epithelium
• Excretion
Removal of drug/metabolites from the body
Mostly in urine, but also via bile/faeces, sweat, tears, saliva, exhaled air & milk

Question 2

What is drug clearance?

Answer 2

• The volume of plasma cleared of drug per unit time
• A constant clearance for drugs following 1st order kinetics
• For a drug that is removed by liver metabolism and kidney excretion
• Plasma clearance = Renal artery clearance and Hepatic clearance

Question 3

Why is studying metabolism and excretion important?

Answer 3

• Dosing issues
Metabolism / clearance determine the amount of drug available at site of action,
Time taken for a drug to reach steady state levels
• Safety issues
Metabolism produces new chemical entities that may have their own effects
Components of racemic molecules (D/L) handled differently – the concentration of a D form drug can sometimes be double the concentration of an L form drug.
• Knowledge can aid design of future drugs
• Drug metabolites measured in substance abuse tests
• As the drug is being metabolised it reduces the pharmacology activity of the drug.

Question 4

Give further details about drug metabolism

Answer 4

• Drug removal begins immediately
• Most undergo metabolism prior to removal – to increase excretion
• Loss of (or reduced) biological activity
increase polarity/less receptor binding
• Some drugs are “activated” by metabolism (prodrug)
e.g. enalapril into active form enalaprilat by esterases
• Some drugs eliminated unchanged
e.g. digoxin
• Toxic metabolites

Question 5

Describe phase 1 of drug metabolism

Answer 5

Phase 1 introduces chemically reactive groups
• Main process is oxidation within the liver
• Addition of oxygen molecules to carbon, nitrogen, sulphur molecules in drug structure
• Carried out by cytochrome P450 enzymes (huge superfamily of enzymes in liver)
bind drug and molecule oxygen
oxidation of drug occurs through one oxygen atom, the other oxygen atom is reduced to water
• Other reactions: hydrolysis, hydration etc
• These show the different isoforms of the cytochrome enzymes.

Question 6

Describe phase 2 drug metabolism

Answer 6

• Phase 2 increases water solubility of drug for excretion
conjugates the Phase 1 product with an endogenous substance through production of stable covalent bonds
e.g. glucuronidation (reaction with glucose)

Question 7

How is paracetamol metabolised

Answer 7

• Paracetamol does not do this.
• It does not need phase 1 reaction, it can be metabolised using phase 2 reactions, by adding a sulphate or glucuronide group.
• SATURATION: occurs when there is ‘to much’ paracetamol, therefore metabolism undergoes a different pathway.

Question 8

Describe excretion via the kidney

Answer 8

• Glomerulus filtration
Filters <20kDa molecules
Amount excreted depends on levels of drug bound to plasma proteins
• Reabsorption
As molecules pass through tubules they are concentrated, creating large concentration gradient for reabsorption – hence need to make drugs water-soluble
• Tubular secretion
Acid/base molecule carriers transporting molecules into tubular fluid
Lower levels of unbound drug in plasma, pushing reaction for plasma proteins to release more free drug for secretion by carriers
Excretion = filtration – reabsorption + secretion

Question 9

Describe renal clearance

Answer 9

• The volume of plasma cleared of drug per unit time in one pass through the kidney
• The drug is cleared from blood and appears in urine
• E.g. the plasma [drug] is 10 µg/ml; drug is appearing in urine at 500 µg/min, then its renal clearance is 50 ml/min
• ↓ renal elimination  ↑ plasma half-life