L7: Drug metabolism

Question 1

What is drug metabolism

Answer 1

Enzyme catalysed chemical change to the drug molecule which is major route of removal for lipophilic drugs
- Typically make lipophilic drugs into polar metabolites which enhance excretion through urine or bile, as they are less likely to diffuse into cells- and also reduce distribution in the body.

Question 2

Why is drug metabolism important

Answer 2

• Directly influences the concentration of drug in the blood over time- and therefore the pharmacological effect.
• If the metabolism is faster, bioavailability is decreased due to first pass metabolism and rate of elimination is increased- therefore lower cmax, less time in the body.

(Also maj route of elim, can lead to drug activation or toxic metabolites)

Question 3

What are the different types of metabolites that can be produced in why drug metabolism is important

Answer 3

• Inactive form of parent drug
• Active form of prodrug which increases drug activity
• Toxic intermediate substance when there is build up due to overdose - can cause cell damage/death

Question 4

How is the expression of drug metabolising enzymes affected (2) in why drug metabolism is important

Answer 4

• Some drugs can induce and inhibit the expression of enzymes which can alter the metabolism of itself or other drugs- therefore Drug-drug interactions
• There is variability in the expression of these enzymes from person to person due to - diet, age, disease state and organ function, etc : patient variability

Question 5

Where are drugs metabolised

- a single drug may be metabolised by multiple routes/ multiple enzymes

Answer 5

Liver - first pass metab of oral drugs
Intestinal wall: CYP450 enzymes
GI tract: gut bacteria and proteases-- drugs with poor absorption/excretion in bile.
Plasma: Esterases (prodrug activation)
Lungs: Metabolism of aerosol sprays

Question 6

What are the 3 phase 1 metabolism reactions

Answer 6

Phase 1: usually inactivate drug by uncovering group on the drug

Oxidation (add O through loss of H+), Reduction (adding H+ w/w/out loss of O2)

Hydrolysis water molecule added usually resulting in bond cleavage.

Question 7

What reaction is Cytochrome P450 (CYP) enzymes commonly known for catalysing

Answer 7

Monooxygenase reaction where O2 + H+ + NADPH is added to the drug and this makes oxidised drug + water and NADP+.
Requires O2, NADPH and cytochrome P450 reductase for electrons.

Question 8

Which families of CYP and 5 isotypes involved in drug metabolism

Answer 8

CYP family 1-3

CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4

Question 9

What upregulates or downregulates CYPS

Answer 9

• Drugs that inhibit enzymes: prevent metabolism–> increased toxicity, reduced activation of prodrugs
• Environmental factors or drugs can increase expression of some CYP enzymes- enhance metabolism–>reduce drug activity, increase toxic metabolite buildup
• Difference in gene expression/polymorphism can cause function of CYP enzymes to differ amongst individuals

Question 10

What are the clinically relevant substrate and drug interactions for CYP1A2

Answer 10

substrate: theophylline, caffeine
DI: inhibited by cimetidine, increased expression induced by tobacco- greater metabolism

Question 11

What are the clinically relevant substrate and drug interactions for CYP2E1

Answer 11

Substrate: ethanol, paracetamol
DI: chronic ethanol consumption increases CYP2E1-> more formation of paracetamol toxic metabolite

Question 12

What are the clinically relevant substrate and drug interactions for CYP2D6

Answer 12

Substrate: debrisoquine, tricyclic antidepressants- amitriptyline, codeine (–>morphine)

Drug interaction: fluoxetine inhibits.

Genetic polymorphisms for this enzyme means that some people have fast versions and slow versions. This means that dose adjustments need to be made so fast ones have higher dose, slow ones have lower dose

Question 13

What are the clinically relevant substrate and drug interactions for CYP2C9

Answer 13

Substrate: S-warfarin
DI: cimetidine inhibit metabolism. Genetic polymorphisms alter ability of patients to metabolise warfarin- dose adjustment

Question 14

What are the clinically relevant substrate and drug interactions for CYP2C19

Answer 14

Substrate: omeprazole, clopidogrel (prodrug)
DI: omeprazole also inhibits CYP2C19 reducing its own metabolism and other substrates
Genetic polymorphisms:

Question 15

What are the clinically relevant substrate and drug interactions for CYP3A4 -
major enzyme in liver, intestines, kidney, lung, uterus, placenta and does 30% of drugs

Answer 15

Substrate: Erythromycin, simvastatin, felodipine.

DI: ketaconazole, grapefruit juice inhibit the metabolism
Rifampicin, St John’s wort induce more enzymes expressed

Genetic polymorphisms exist but don’t lead to significant interindividual variability

Question 16

What is the phase two reaction

Answer 16

Phase 2 Conjugation: Addition of endogenous substrate to increase molecular mass, polarity, water solubility.
- facilitates excretion through bile/urine.
- and most cases terminate biological activity
Glucuronidation is a major pathway, and often follow CYP catalysed reaction but not all.
-Less prone to drug-drug interactions/ genetic polymorphisms because overlapping substrate specificity and large capacity- lots of enzymes can do the same job.