Drug metabolism and excretion

Question 1

What is drug elimination?

Answer 1

The irreversible removal of a drug from the body

Question 2

How are drugs removed from the body?

Answer 2

Metabolised in the liver

Excretion of unchanged drugs (kidneys) or through expiration and the gut

Question 3

How is metabolism carried out?

Answer 3

Metabolism is carried out by enzymes, and can take place anywhere in the body. However, the vast majority of small molecule drugs are metabolised in the liver.
Occurs in 2-phase process

Question 4

What is the 2-phase process of metabolism?

Answer 4

Phase 1 - modification:
Involves cytochrome P450 - dependent mixed function oxidase.
Commonly causes an oxidation, reduction or hydrolysis.
Creates highly-reactive compounds

Phase 2 - conjugation:
Joins (conjugates) the Phase 1 metabolite onto another molecule in order to make it charged. Such groups include; glutathione (GSH), sulfate, glycine, or glucuronic acid

Question 5

What are Cytochrome P450s?

Answer 5

Haem containing enzymes
metabolise a wide range of molecules
important sites of drug interaction via substrate inhibition.

Question 6

give an example of P450 interaction.

Answer 6

Amiodarone is a substrate for CYP1A2 which metabolises caffeine.
Therefore when taken, this slows the metabolism of caffeine meaning that its effects last longer.

Question 7

Why is a charge added onto the metabolite during phase 2 conjugation?

Answer 7

Adding a net charge to a metabolite is done to aid renal clearance or excretion.

Question 8

What is an active metabolite?

Answer 8

Just because a drug is no longer present, the effect of dosing may continue because metabolites may be active, and hence either toxic or therapeutic.

Question 9

What is a prodrug?

Answer 9

A drug which converts from inactive to active drugs

Question 10

Give some examples of active metabolites

Answer 10

Prodrugs
Morphine
Pethidine

Question 11

Give an example of metabolism of paracetamol

Answer 11

Phase 1:
N-hydroxylation by CYP2E1 or CYP1A2 forms NAPQI
Phase 2:
Conjugation to glutathione.

In overdose, conjugation cannot proceed quickly enough and NAPQI accumulates and results in liver failure

Question 12

What are the different excretion/elimination routes for drugs and metabolites?

Answer 12

Renal - particularly by filtration in the glomerulus and secretion in the PCT

Hepatic/biliary and hence faecal or enterohepatic elimination.

Others:
sweat
milk
breath

Question 13

How does drug elimination work in the kidney?

Answer 13

About 4% of the drug in the plasma is filtered in the glomerulus.
Charged or polar molecules are trapped in the tubules and hence lost in the urine.
Some drugs are actively transported into the tubules by acid transporters or organic base transporters.

Question 14

What happens to the concentration of a substance added to a body compartment over time inside the body?

Answer 14

Rate of removal of a drug from the body is often proportional to its drug concentration

Question 15

What is the half life of a drug?

Answer 15

The time take for the drug concentration to fall to 1/2 of its initial value

Question 16

How can you express the concentration of a drug in a compartment?

Answer 16

C= Cmax x e^-kt

Question 17

How can we work out the new drug concentration over time?

Answer 17

C = Cmax(1/2)^t/t(1/2)

Question 18

What is the concept of zeroth order pharmacokinetics?

Answer 18

That the rate of drug removal over time is constant (eg. ethanol)

Question 19

Explain the zeroth order kinetics of ethanol.

Answer 19

High(ish) ethanol concentration - k is approx. 10g/hr. The clearance of ethanol is “zeroth order” because the concentration is so high that the hepatic enzymes are saturated and hence working at their maximum rate, regardless of the ethanol concentration, until the concentration gets very low