Drug Metabolism

Question 1

What does metabolism tend to do to a drug?

Answer 1

Convert drugs (usually lipid soluble) to metabolites (less lipid soluble + easier to excrete)

Question 2

What is hepatic first pass metabolism?

Answer 2

Metabolic conversion of drug into something different before the drug enters the circulation.
In other words – the effect that occurs the very 1st time the drug passes through the liver.

Question 3

What effect does extensive first pass metabolism have on bioavailability?

Answer 3

Extensive 1st pass metabolism -> low bioavailability

Question 4

How can you avoid hepatic first pass metabolism?

Answer 4

Giving a drug intravenously

Question 5

What are the 3 types of reaction that fall under phase I reactions?

Answer 5

Oxidation + Reduction (create new functional groups)

Hydrolysis (unmasks functional groups)

Question 6

What is the purpose of Phase I metabolism?

Answer 6

Release or uncover functional groups that can be used in phase II reactions

Question 7

How do phase I reactions affect polarity of the drug?

Answer 7

Little effect on polarity of a drug

Question 8

What enzyme system is extremely important to drug metabolism? Where are these enzymes found?

Answer 8

Cytochrome P450
Mainly found on SER of hepatocytes in the liver
Capable of metabolising xenobiotics

Question 9

What are the substrates and products of the Cytochrome P450 mediated oxidation reaction?

Answer 9

Substrates = drug, NADPH, oxygen (O2), protons (H+) 
Products = hydroxylated drug, NADP+, water

Question 10

What at the 6 types of phase II reactions?

Answer 10

Glucuronidation 
Acetylation 
Sulphation 
Glutathione Conjugation
Methylation 
Amino Acid Conjugation

Question 11

State the conjugating agents for glutathione conjugation, glucuronidation, acetylation and sulfation

Answer 11

Glutathione
UDP-glucuronic acid
Acetyl CoA
3’-phosphoadenosine-5’phosphosulphate

Question 12

What effect do phase II reactions have on the drugs?

Answer 12

Make drugs more polar + water-soluble (less lipid-soluble) so they can be excreted more easily

Question 13

What are some features of conjugating agents?

Answer 13

Large
Polar
Endogenous

Question 14

What is the most common type of phase II reaction? When is it most likely to occur?

Answer 14

Glucuronidation (addition of a sugar)

Low affinity/high capacity- more likely to occur at high drug doses

Question 15

What is the importance of glutathione conjugation?

Answer 15

Glutathione is conjugated with electrophiles so they can be excreted
Electrophiles are damaging species, often generated during metabolism – must be removed because they can cause DNA + protein damage

Question 16

State an important property of the conjugates formed from glucuronidation and its impact on its excretion.

Answer 16

Large MW products= problem with glomerular filtration

High MW molecules are often excreted in the bile

Question 17

What is the conjugating agent in acetylation and what is the product?

Answer 17

Acetyl CoA

Product= acetylated derivative of the drug + CoA (CoA then goes into intermediary metabolism)

Question 18

What is the conjugating agent for methylation?

Answer 18

S-adenosyl methionine

Question 19

What are the properties of the derivative formed in sulfation?

Answer 19

Product= sulfuric acid derivative of the drug

= very polar + water-soluble

Question 20

What effect does drug metabolism have on biological half-life, duration of exposure and accumulation of drugs in the body?

Answer 20

Decreases biological half-life
Decreases duration of exposure
Prevents accumulation of drugs in the body
Potency of biological activity can be altered
Toxicology can be governed

Question 21

Why would you want a drug to be lipophilic?

Answer 21

So it can access tissues + have a therapeutic effect

Question 22

Why would you wan a drug to be water soluble?

Answer 22

So it is retained in the blood + delivered to excretion sites

Question 23

What is the most common Phase 1 metabolism?

Answer 23

Oxidation

often start with hydroxylation

Question 24

What types of metabolites may be produced from Phase 1 metabolism?

Answer 24

Inert metabolite
Active metabolite (prolongs effects)
Active metabolite (prodrug)

Question 25

When is sulfation most likely to occur?

Answer 25

Sulfation is high affinity/ low capacity

More likely to occur at low drug doses

Question 26

What happens in a paracetamol OD?

Answer 26

Oxidation occurs to produce NAPQI (electrophile)
Electrophiles are very reactive (no issue if glutathione present)
With OD, all stores of glutathione are used up leaving very reactive phase 1 electrophile metabolite which can cause liver damage