Lecture 7: Drug metabolism

Question 1

What is drug metabolism?

Answer 1

Metabolism is the biotransformation of drugs
- Enzyme catalysed chemical change to the drug molecule; either building a molecule up (more polar for elimination) or breaking down

Question 2

What sort of metabolites does drug metabolism usually produce?

Answer 2

Biotransformation reactions typically generate more polar metabolites

• Most drugs are lipophilic
• Enhance excretion through urine or bile
• Metabolites are less likely to diffuse into cells

Question 3

What happens to most drugs which are lipophilic in the kidneys?

Answer 3

Most drugs are lipophilic and will not be renally excreted, as the fraction of drug that is filtered in the glomerulus will be reabsorbed back into the bloodstream. For elimination from the body, these drugs are generally metabolised into more polar metabolites that can then be excreted from the body in the urine (or the bile)

Question 4

Why is drug metabolism important?

Answer 4

Drug metabolism can directly influence the concentration-time profile in the body
- Concentration determines effect

Major route of elimination
- Generally inactivates drugs

Can increase drug activity
- Activation of prodrug (codeine to morphine)

Production of toxic metabolites
- I.e paracetamol

Can explain drug-drug interactions

Source of between patient variability

NB: Rapidly metabolised high extraction drug will achieve lower plasma concentrations than slowly metabolised low extraction drugs.

Question 5

Describe how paracetamol metabolism can lead to toxic metabolites:

Answer 5

Overdose of paracetamol results in the saturation of glutathione conjugation of a reactive metabolite, leading to buildup of a reactive metabolite, which can cause liver cell death.

Question 6

What are some possible sites of drug metabolism?

Answer 6

• Liver
• Intestinal wall, CYP450 enzymes
• Gi tract, gut bacteria and proteases
• Plasma esterases
• Lungs, metabolism of aerosol sprays

Question 7

Write some notes on liver metabolism:

Answer 7

Major site of liver metabolism

• First pass metabolism of oral drugs (i.e morphine)
• May necessitate dosing by other routes

Question 8

What are some possible metabolism reactions?

Answer 8

• Oxidation (Addition of O with loss of H)
• Reduction (add H w or w/o loss of O)
• Hydrolysis (Water molecule is added)
• Conjugation

Question 9

Write some notes on conjugation:

Answer 9

Conjugation

• Addition of endogenous substrate to increase molecular mass, polarity, water solubility
• Glucuronide, sulphation, acetylation, methylation, glutathionylation

Question 10

Write some notes on the cytochrome p450 enzymes:

Answer 10

Superfamily of metabolism enzymes

• many genes
• CYP families 1-3 are predominantly involved in drug metabolism

Most common drug metabolism enzymes

• Catalyse oxidation reactions
• 5 isoforms metabolise approx 90% of drugs

Question 11

What is the most common reaction of cytochrome P450?

Answer 11

Most common reaction is a monooxygenase reaction

- Requires O2, NADPH and cytochrome P450 reductase

Question 12

What can alter CYP mediated drug metabolism?

Answer 12

• Some drugs inhibit CYP -> Prevent the metabolism of itself or co-administered drugs = Increased toxicity, Reduced activation of prodrugs
• Some drugs or the environment can upregulate or downregulate CYP enzymes
• Function of CYP enzymes differs amongst individuals
• > Differences in gene expression and genetic plymorphism

Question 13

What are some more important CYP isoforms?

Answer 13

CYP1A2
CYP2E1
CYP2D6

Question 14

What are the clinically relevant substrates of CYP1A2 isoform and its drug interactions:

Hint: Adenosine

Answer 14

CYP1A2

• Clinically relevant substrates: Theophylline, caffiene
• Drug interactions: Cimetidine (inhibition), tabacco, BBQ meat, cruciferous veges (induction)

Question 15

What are the clinically relevant substrates of CYP2E1 isoform and its drug interactions?

Hint E = Ethanol

Answer 15

• Clinically relevant substrate: Ethanol, paracetamol
• Drug interactions: Chronic ethanol consumptioon increases CYP2E1 expression (increases toxic metabolite of paracetamol production)

Question 16

Discuss the substrates, drug interactions and gene considerations of CYP2D6 isoform:

D = (antiDepressants, coDiene)

Answer 16

• Clinically relevant substrate: Debrisoquine, tricyclic antidepressants, codiene
• Drug interaction: Fluoxetine (Inhibition)
• Over 100 allelic variations (inter-individual variation) (ppor through to ultrarapid metabolisers)

Therefore: Drug companies try to avoid compounds that are substrates for CYP2D6

Question 17

Discuss the CYP2C9:

Hint: Cimetidine keeps your blood thin

Answer 17

Clinically relevant substrate: S-warfarin
Drug interactions: Cimetidine inhibition of warfarin metabolism
Genetic polymorphisms alter ability of patients to metabolism warfarin

Question 18

Discuss the CYP2C19:

Hint: Omeprazil hoists its own petard

Answer 18

Clinically relevant substrates: Omeprazil,Clopidogrel

Drug interactions: Omeprazil also inhibits this (CYP2C19) reducing metabolism of co-administered CYP2C19 substrates

Genetic polymorphisms (covered later)

Question 19

Discuss drug interactions of CYP3A4:

Hint: simvAstatin

Answer 19

• Major enzyme for 30% of drugs currently on the market
• Liver, Intestines, kidneys, lung, placenta, uterus

Clinically relevant substrates: Erythromyocin, simvastatin, felodipine

Genetic polymorphisms do exist but dont lead to significant interindividual variability

Drug interactions: Erythromycin, grapefruit juice, rifampicin, st johns wart

Question 20

Write some notes on conjugation reactions:

Answer 20

Less prone to drug-drug interactions and genetic polymorphisms due to large capacity and overlapping substrate specificity

If one enzyme is inhibited often another can take over and do the job

Question 21

What are things to consider when it comes to drug metabolism?

Answer 21

• Organ function
• Genetics
• Diseases
• Other drugs
• Diet, lifestyle
• Age
• Sex
• Pregnancy