ADME Three

Question 1

What is the most important site of drug metabolism?

Answer 1

The Liver

Question 2

What places in the body can drug metabolism occur?

Answer 2

Liver
GI tract- bacteria and proteases
Intestinal walls- CYPs
Plasma- esterases (i.e breaks down acetylsalicylsate-aspirin)

Question 3

What does drug metabolism result in?

Answer 3

Drug is converted by metabolising enzymes into water soluble metabolite

Question 4

Why do metabolic enzymes convert drugs into water soluble metabolite?

Answer 4

Water soluble metabolite is:

• less likely to diffuse into cells and reach receptors (relies on passive diffusion to do this)
• Favours increased excretion in urine or bile(very large mw weight)
• Usually abolishes activity and terminates drug action

Question 5

What are the exceptions to metabolite enzymes that breakdown drugs but dont deactivate them?

Answer 5

• Can promote activity i.e prodrugs: acetylsalicylate
• No change in activity: diazepam into nordiazepam
• Produces toxic metabolites (paracetamol-only if too much)

Question 6

How many phases of drug metabolism are there?

Answer 6

Up to two

Question 7

What is phase 1 of drug metabolism?

Answer 7

Addition or uncovering of a reactive group

i.e
Oxidation
Reduction
Hydrolysis

Makes molecules more susceptible to phase two reactions

Question 8

What is phase two?

Answer 8

Conjugation of endogenous molecule with drug

i.e
Glucurnoide
Sulphate
Glutathione

Makes the molecule more polar, ideal for substrates in active transport and excretion (more water soluble)

Question 9

What is the most important reaction for phase one metabolism?

Answer 9

Oxidation is the most important reaction for phase one metabolism of all drugs

Question 10

What are the most important enzymes for the oxidation reactions?

Answer 10

CYPs = cytochrome P450 mixed function oxidase systems

Question 11

Of the CYPs which are the most involved?

Answer 11

CYP1, CYP2 and CYP3

Question 12

What does the oxidation reaction require?

Answer 12

O2, NADPH and cytochrome P450 reductase- huge range of substrates

This also oxidases a range of endogenous compounds.

Drug+ O2+H+ + NADPH forms Oxidised drug+H2O+NADP+

Question 13

Whats an example of phase one action?

Answer 13

Phenytoin: (lipophylic)

Phase one: Hydroxylation, (OH forms) becomes slightly water soluble but INACTIVE now

Phase two: Conujugation by UDP glucuronosyl transferase (addition of Uridine Diphosphate Glucuronide)

Now is inactive and very water soluble.

Question 14

So what metabolic processes can a drug directly undertake?

Answer 14

Phase one: can be excreted sometimes, otherwsie followed by phase two then excretion

Or

Straight to phase two and excretion (formation of a drug conjugate.)

Question 15

What are the two methods of excretion?

Answer 15

Bile excretion (faecal excretion)
Renal excretion (urine)

Question 16

What are the factors influencing drug metabolism?

Answer 16

Mainly: The patients genetic constitution

Also:
Organ function
Diseases +other drugs
Diet+cigarettes+alcohol 
age+sex+pregnancy

Question 17

How many people dont respond to a drug?

Answer 17

1 in 5

Question 18

How many people have a toxic response to a drug?

Answer 18

20-30%

Question 19

How many people actually respond to the drug in the intended way?

Answer 19

50-60%

Question 20

Whats an example of a drug that neonates have reduced metabolism for?

Answer 20

Theophylline, as they get older the half life decreases

Question 21

As people age how does their body clearance change?

Answer 21

Drug Clearance ability decreases with age, but not too clinically relevant

Question 22

Using theophylline what is the half life in several population categories?

Answer 22

Neonates = 30-60hrs
Children = 2-4hrs
Adults (non-smokers) = 6-10hrs
Adults (smokers) = 4-6hrs

Do get the same effect the drug maintenance dose must vary between populations

Question 23

What happens to enzymes once exposed to an inducing agent?

Answer 23

When exposed to an inducing agent, enzyme synthesis initiated within 24hr of exposure, increasing over 3-5days.

This inducing effect causes increased enzymes that results in the removal of dug from a system faster

Question 24

Once inducing agent is discontinued what happens to the induction effect?

Answer 24

Effect decreases over 1-3 weeks after inducing agent is discontinued.

Question 25

What environmental factors lead to the inducing effect?

Answer 25

Smoking
Eating BBQ meat
Ethanol

Barbiturates
Rifampicin

Question 26

What happens when drug metabolism is inhibited?

Answer 26

Rapid onset within 1 day

Exaggerated response with increased risk of toxicity

Question 27

What are some examples of reversible inhibitors of drug metabolism?

Answer 27

Grapefruit juice

Lead (complex with CYP)

Question 28

The induction of enzymes control what?

Answer 28

The induction of enzymes in the gut wall and liver determine the amount of drug that makes it into the blood stream from administration (bioavailibility)