Drug metabolism

Question 1

Why would you want a drug to be lipophilic?

Answer 1

So drugs can access tissues – therapeutic effect

Question 2

Why would you want a drug to be water soluble?

Answer 2

Retained in the blood and delivered to excretion sites

Question 3

Why is metabolism of drug required>

Answer 3

We design relatively lipid soluble drugs.

Body alters the drug to make it less lipid soluble and easier to excrete.

The process of metabolism involves the conversion of drugs (usually quite lipid soluble) to metabolites (usually less lipid soluble and easier to excrete).

Question 4

Drug metabolism involves 2 kinds of biochemical reactions- which are?

Answer 4

Phase 1 – main aim is to introduce a reactive group to the drug (increase polarity)

Phase 2 – main aim is to add a water soluble conjugate to the reactive group

Question 5

what is the major organ for drug metabolism?

Answer 5

liver

Question 6

define hepatic first pass metabolism

Answer 6

metabolic conversion of the drug into something that is different before the drug enters the general circulation

OR
the effect that occurs the very first time the drug passes through the liver

Question 7

What happens to the bioavailability if metabolism of the drug is extensive?

Answer 7

If the metabolism is extensive you may only release a small amount
of the active drug into the systemic circulation (low bioavailability)

Question 8

Explain how phase 1 occurs

Answer 8

All about releasing or making functional groups

Oxidation/reduction creates
new functional groups

Hydrolysis unmasks them.

Important – functional group
serves as a point of attachment
for phase II reactions

Question 9

What enzyme does the liver contain and what is it used for in phase 1 reactions?

Answer 9

The liver contains an enzyme system called
cytochrome P450
•In humans there are
57 enzymes
involved in the cytochrome P450 system
•This system has the
capability to metabolise loads of xenobiotics

This is the main system involved in Phase I oxidising reactions
•It is involved in the metabolism of MOST drugs

Question 10

what is the most common phase 1 metabolism?

Answer 10

oxidation (which often starts with hydroxylation)

Question 11

be able to recognise hydroxylation, reduction and oxidation

Answer 11

see slide

Question 12

Phase 1 metabolism converts the active parent drug into?

Answer 12

Phase I reactions often
inactivate drugs (to form inert metabolites) but they can also produce active metabolites.
Metabolism can also convert inactive parent drugs into active metabolites.
With prodrugs, you administer it as something that is not pharmacologically
active so you rely on the liver to convert the prodrug into something that’s pharmacologically active

Question 13

Phase 2 metabolism defined

Answer 13

there is a discrete number of these reactions

•The conjugate that is formed is almost always 
inactive
•It is less lipid soluble
•It is more polar
•It is easier to excrete

Question 14

What do you need for phase 2 metabolism reactions?

Answer 14

conjugating agent

Question 15

what are conjugating agents?

Answer 15

conjugating agents are usually large polar and endogenous chemicals that are used in the reactions
they target specific types of functional groups

Question 16

What is the most common phase 2 metabolism reaction and what does it react with?

Answer 16

Most common Phase 2 metabolism = glucuronidation

Glucuronidation is low affinity/high capacity – more likely to occur at high drug dosages.

Glutathione reacts with electrophiles

Question 17

What is sulfation and what happens?

Answer 17

Other Phase 2 metabolism pathways = sulfation

Sulfation is high affinity/low capacity – more likely to occur at low drug dosages.

Question 18

What is glutathione conjugation?

Answer 18

Other Phase 2 metabolism pathways = glutathione conjugation

Drug needs to be electrophilic to be conjugated or biotransformed to an
electrophilic conjugate

Question 19

How do you convert paracetamol to an electrophile?

Answer 19

Losing hydrogen

Question 20

What are the problems with electrophiles?

Answer 20

Problem – electrophiles are extremely reactive

Paracetamol overdose – glutathione stores overwhelmed!!

Question 21

Importance of drug metabolism

Answer 21

The biological half-life of the chemical is decreased.

The duration of exposure is reduced.

Accumulation of the compound in the body is avoided.

Potency/duration of the biological activity of the chemical can be altered.

The pharmacology/ toxicology of the drug can be governed by its metabolism.