Drug metabolism and excretion

Question 1

What is drug elimination?

Answer 1

The irreversible removal of drug from the body.
This is through metabolism - primarily by the liver
Excretion - of unchanged drug, by the kidney.

Question 2

How does metabolism occur?

Answer 2

Carried out by enzymes, anywhere in the body.
Most small molecules are metabolised in the liver.
2 phases - modification and conjugation.

Question 3

What is modification?

Answer 3

Causes an oxidation, reduction, or hydrolysis to create highly-reactive compounds.
Usually involves a cytochrome P450-dependent mixed function oxidase.

Question 4

What are cytochrome P450s?

Answer 4

CYP and mixed-function oxidases are haem containing enzymes.
They metabolise a wide range of different molecules.
Important for drug interactions through substrate inhibition, non-substrate inhibition e.g. quinidine, and induction.
May involve other enzyme systems such as alcohol dehydrogenase, monoamine oxidase - breaks down neurotransmitters.

Question 5

What is important about CYP?

Answer 5

Lots of different CYPs, so lots of diversity in the way people metabolise drugs.
Can be used for personalised therapies.

Question 6

What is substrate inhibition of P450?

Answer 6

Amiodarone is a substrate for CYP1A2 enzyme, which also metabolises caffeine.
So amiodarone will slow down the metabolism of caffeine.
Used in treatment of heart disease and asthma.

Question 7

What is induction of P450?

Answer 7

Barbiturates
Rifampicin
Phenytoin is an anti-epileptic drug that increases the activity of CYP2C9. This increases the rate of metabolism of its substrates - ibuprofen, losartan, carvedilol.

Question 8

What is conjugation?

Answer 8

Joins the phase 1 metabolite onto another molecule to make it charged.
Groups include glutathione (GSH), sulfate, glycine or glucuronic acid.

Question 9

What is the effect of conjugation?

Answer 9

Adding a net charge to a metabolite can aid renal clearance (excretion).
The kidney filters compounds which then go through a tubule system, and have to be charged to remain in the system to be excreted.

Question 10

What are active metabolites?

Answer 10

Metabolites can be biologically active. The effect of dosing may continue if it is active, and be toxic or therapeutic.
e.g. morphine, prodrugs and pethidine.

Question 11

What are prodrugs?

Answer 11

Convert inactive drugs to active drugs in the liver.

Question 12

What is morphine?

Answer 12

Morphine is active but converted to morphine-6-glucuronide metabolite, which is also active, and acts on the same receptors as morphine.
So morphine will continue to have an effect even when it is not in the body.

Question 13

What is pethidine?

Answer 13

Pethidine is active, but converted to norpethidine, which is epileptogenic (seizure causing).
Repeated dosing causes it to build up and cause seizures.
So pethidine is only used as a single dose.

Question 14

What is the metabolism pathway for paracetamol?

Answer 14

Main pathway:
Phase 1: N-hydroxylation by CYP2E1, CYP1A2 or CYP2D6 to form NAPQI.
Phase 2: Conjugation to glutathione.

Question 15

What does a paracetamol overdose do?

Answer 15

Conjugation pathways become saturated, because limited by enzyme rate.
Paracetamol concentrations increase.
Phase 1 generates NAPQI, which is toxic to the liver, reacts with proteins and nucleic acids which can kill the liver cells.

Question 16

What are the excretion routes for drugs and metabolites?

Answer 16

Renal - filtration in the glomerulus and secretion in the proximal tubule (urine).
Hepatic/biliary
Other - Sweat, milk or breath.

Question 17

How does drug elimination in the kidney occur?

Answer 17

20% of plasma of blood flow to kidney is filtered in the glomerulus.
Charged or polar molecules are trapped in the tubules and lost in the urine.
Some drugs are actively secreted into tubules by transporters.

Question 18

How are drugs secreted by transporters?

Answer 18

Acid transporters - for penicillin, uric acid.
Organic base transporters - for pethidine, quinine.
If drugs are secreted by the same transporter they can compete and so slows excretion.

Question 19

What is hepatic drug excretion?

Answer 19

Drugs enter into bile then into gut for enterohepatic circulation, or elimination through faeces.

Question 20

How can the drug excretion be quantified?

Answer 20

The drug is added from outside the body.
The body here is a single compartment, equal to the volume of distribution.
There is then excretion and metabolism.

Question 21

What is the rate of change of drug concentration?

Answer 21

This is equal to the drug concentration to a power.
dC/dt = -kC^n
Power, n, is the order of elimination of metabolism, usually 1st order.
So, dC/dt = -kC

Question 22

What is the derived equation for drug concentation?

Answer 22

C = Cmax e^-kt
Drug concentration = maximum concentration x number to power of rate constant x time.
see picture

Question 23

What is half life?

Answer 23

The time taken for the drug concentration to fall to 1/2 its initial value.

Question 24

What is the equation for half-life?

Answer 24

t1/2 = ln(2) / k or 0.6931/k

Question 25

What is the rearrangement of exponential decay?

Answer 25

C=Cmax (1/2) ^t/t1/2
see picture

Question 26

What is zeroth order kinetics?

Answer 26

Things to the power of 0 = 1, rate of change of drug concentration is constant.
Happens when enzymes saturate - it is a maximum rate.

Question 27

What is an example of zeroth order kinetics?

Answer 27

High concentration is taken of ethanol so clearance is 0 order because the hepatic enzymes are saturated.
So if more than 1 drink of ethanol is taken per hour, will be zeroth order.