Hepatic Drug Metabolism

Question 1

What are the 4 phases of pharmacokinetics?

Answer 1

ADME:

A: Absorption

D: Distribution

M: Metabolism

E: Excretion

Question 2

What does drug metabolism do to:

Drug activity

Pro-drugs

Active metabolites

Answer 2

Conversion of active drugs to inactive compounds:

• Most common fate of active drugs

Pro-drugs: activated by metabolism in liver

Inactive metabolites: converted to active metabolites.

Question 3

What can conversion of a drug to an inactive metabolite in the liver promote in the kidneys?

Answer 3

Excretion of the inactive metabolite

Question 4

What is first pass metabolism?

What effect does this have on bioavailability?

Answer 4

= the extent of drug metabolism occuring before the drug has reached the systemic circulation.

Drugs administed orally are absorbed through the wall of the GI tract and carried via the hepatic portal system and undergo first pass metabolism by enzymes in the liver.

Reduces bioavailability as levels reaching the systemic circulation are reduced.

Question 5

Where does the majority of drug metabolism take place?

Answer 5

In the hepatocytes of the liver

Question 6

What is phase 1 metabolism?

Answer 6

Adds a functional group to the drug (e.g. hydroxyl group) to increase the polarity of the drug molecule and makes it a site for phase II conjugation reactions.

Does this by either:

• Oxidation (most common)
• Reduction
• Hydrolysis

Often makes drugs less pharmacologically active

Question 7

What is phase II metabolism?

What types of drug can undergo this reaction?

Answer 7

Conjugation reaction that adds a large chemical group to a functional group on a drug, making the drug more soluble (hydrophilic) to make it more easily excreted. Forms a conjugated metabolite which is usually pharmacologically inactive.

Drugs that are susceptible to this reaction are those that have undergone phase I metabolism or those that already contain a functional group which makes them suitable for conjugation.

Question 8

What is phase III transport?

Answer 8

The conjugated metabolite is transported out of the hepatocyte either into the systemic circulation for renal excretion or across the canalicula membrane into the bile for excretion via the faeces.

Question 9

What are cytochrome P450 enzymes?

What are their roles?

What do they require?

What is the mixed function oxidase system?

Answer 9

Haem proteins that catalyse many of the phase I metabolism reactions.

Require the presence of molecular oxygen, cofactor NADPH and NADPH cytochrome P450 reductase to function. This together is the mixed function oxidase system.

Question 10

How do cytochrome P450 enzymes oxidise drugs?

Answer 10

Catalyses the transfer of one oxygen atom to the substrate (drug) while the other atom is reduced to water

DH + O₂ + NADPH + H⁺ → DOH + H₂O + NADP⁺

Question 11

Which is the most abundant cytochrome P450 enzyme in the liver?

Answer 11

CYP3A

Responsible for the greatest number of drug metabolism reactions.

Question 12

What other phase I reactions exist other than oxidation?

Answer 12

Reduction:

Oxidations that do not involve cytochrome P450 enzymes:

• e.g. Monoamine oxidase inactivates biologically active amines e.g. NA and 5-HT.
• Ethanol is oxidised by alcoholic dehydrogenase

Hydrolytic reactions

• Occur in plasma and other tissues
• E.g. aspirin is hydrolysed to salicylic acid.

Question 13

Where do phase II reactions commonly occur?

What groups are often added to the drugs?

Answer 13

Occurs mainly in the liver, can also occur in the lungs and kidneys.

Most common groups involved are glucuronyl, acetyl, methyl, sulphate and glutathione.

Question 14

How are hydrophilic metabolites moved from the hepatocytes into the circulation/bile?

Answer 14

Multi-purpose membrane bound transport carrier systems (efflux transporters) on the lateral membrane and bile canalicula membrane.

Question 15

Give an example of a pro-drug that is activated by phase I metabolism

Answer 15

ACE-inhibitors

Question 16

Give examples of drugs that are not inactivated by metabolism and renal excretion is the main factor determining their duration of action

Answer 16

Digoxin

Atenolol

Question 17

Give an example of a drug that yields a toxic metabolite when undergoing phase I metabolism

Answer 17

Paracetamol

Question 18

How must dosage be adjusted for a neonate?

Why is this?

Answer 18

Dosage of all drugs must be reduced because:

• Hepatic drug-metabolising enzyme systems are immature
• Renal clearance is also inefficient

Question 19

How must drug dosage be adjusted in children?

(1-9 years)

Answer 19

Metabolic clearance in children can be higher than in adults because cytochrome p450 enzymes are mature and relative hepatic blood flow and liver mass are higher.

Dose should be prescribed considering age and body surface area (should be obtained from paediatric dosing handbook)

Question 20

How does hepatic drug metabolism vary with older adults?

Why is this?

How should dose be adjusted?

Answer 20

Older adults may have reduced hepatic drug metabolism capacity (all of ADME reduced), particularly phase I reactions as relative liver mass and blood flow are lower.

Dose should be started at lowest possible therapeutic dose and number of different drugs used should be minimised.

Question 21

Where do drug interactions often occur?

How do some drug reactions occur?

Answer 21

In phase I reactions, drugs may compete for the same metabolising enzyme, affecting the metabolism of the other.

Some drug reactions occur as they inhibit the metabolising enzyme (e.g. CYP3A is inhibited by fluconazole), therefore its ability to metabolise other drugs is reduced, so metabolism and clearance is reduced and effects are increased.

Some drugs may induce the gene expression of metabolising enzymes (CYP3A increased by carbamazepine) which leads to increased clearance of the drug and a subtherapeutic dose.

Question 22

Name some drugs that CYP3A is responsible for metabolising

Answer 22

Calcium channel blockers

Benzodiazepines

HMG-CoA reductase inhibitors

Cyclosporine

Oral contraceptives

Non-sedating antihistamines

Question 23

What are the effects of genetic polymorphisms on drug metabolism?

Answer 23

Within the population, inter-individual variations in the activity of cytochrome P450 enzymes exist.

Mutations in the genes encoding P450 enzymes also alters their expression and therefore the activity of the enzymes.

Poor metabolism (low P450) will cause increased drug efficacy of drugs inactivated by P450 and decreased efficacy of drugs activated by P450. (& vice versa)

Question 24

Give an example of a drug inactivated by cytochrome P450 metabolism.

Which P450 enzyme is responsible?

Answer 24

Omeprazole

CYP2C19

Question 25

Give an example of a pro-drug activated by cytochrome P450 metabolism.

Which P450 enzyme is responsible?

Answer 25

Codeine is converted to morphine by CYP2D6

Question 26

What is the effect of codeine in people with high metabolism and those with low metabolism of the drug?

Answer 26

• Low metabolisers: cannot convert codeine to morphine:
  
  • No/poor therapeutic effect (no pain relief)
  • Exaggerated side effects
• High metabolisers: Opioid toxicity

Question 27

What are the effects of liver cirrhosis on drug metabolism?

Answer 27

Impaired liver function = decreased drug metabolising capacity

Porto-systemic shunting directs drugs away from the liver

Question 28

In what ways can impaired drug metabolising capacity of the liver influence response to treatment?

Answer 28

Increased bioavailability from decreased first-pass metabolism:

• Hepatocyte injury or reduced number
• Hepatocytes may be bypassed by porto-systemic shunting directing drugs away from the liver.
• = increased quantity of drug = increased effect (or decreased effect for drugs that need to be activated in the liver)

Decreased protein binding

• Liver disease may result in decreased plasma protein synthesis = hypoproteinaemia
• Less protein to carry drugs in the circulation.
• = more pharmacologically active unbound drugs to bind to receptors (protein bound drugs inactive whilst bound) = increased effect.