Liver and basic drug metabolism

Question 1

what is the ultimate goal of metabolism?

Answer 1

Ultimate goal is to convert lipophilic substances into more polar and hence more excretable metabolites.

Question 2

______ reduces exposure to potential toxicity

Answer 2

metabolism

Question 3

what are the results of the transformation of lipophilic substances during metabolism?

list 4

Answer 3

More polar metabolite created - ionisable group added

Mol. wt and size often increased

Excretion facilitated

Elimination increased

Question 4

The liver - primary importance for most drugs because______

list 2

Answer 4

Compounds absorbed from the GIT pass through the liver before entering the circulation

High levels of drug metabolising enzymes

Question 5

what are 5 consequences of metabolism?

Answer 5

Biological half-life is decreased

Duration of exposure is reduced

Accumulation in the body is avoided

Biological activity may be changed

Duration of the biological activity may be affected

Question 6

how many phases of metabolism?

Answer 6

2

Question 7

what happens in phase 1 of metabolism?

Answer 7

Introduction of a functional group in order to:

Increases polarity

Creates site for conjugation reaction

Question 8

what happens in phase 2 of metabolism?

Answer 8

Conjugation of a hydrophilic group in order to:

Increases solubility

Enhances elimination

Question 9

list the main enzymes involved in phase 1 metabolism?

Answer 9

Hepatic mixed function oxygenase (MFO) system:-

Cytochrome P450 and FMO.

Question 10

list 3 other phase I enzyme system

Answer 10

alcohol dehydrogenase,

xanthine oxidase (uric acid synthesis),

monoamine oxidase (5-HT, noradrenaline)

Question 11

list most important enzyme for phase 1 drug metabolism?

Answer 11

cytochrome P450 families 1-4:

CYP1; CYP2; CYP3; CYP4

Question 12

MFOs have _______substrates as well

Answer 12

endogenous

Question 13

list 4 facts about cytochrome P450.

Answer 13

Haemoproteins - (apoprotein with a heme prosthetic group)

Located in the membrane of the endoplasmic reticulum

Act in concert with electron donors
(NADPH reductase
Cytochrome b5 reductase)

Movement of charge and electrons across the complex is vital for the catalytic site to function.

Question 14

list the enzyme responsible:

Ethanol __ Acetaldehyde

Paracetamol __ hepatotoxic metabolite.

Tolbutamide ___ excreted metabolite

Answer 14

CYP2E1

CYP2E1

CYP2C10

Question 15

_____is the most abundant P450 in human liver

Answer 15

Cytochrome P450 3A4

Question 16

> 50% of drugs in clinical usage today, that are oxidised, are _____

Answer 16

substrates

Question 17

_____is the most common metabolic reaction, including hydroxylation and dealkylation.

Answer 17

Oxidation

Question 18

________is less common than oxidation reactions - microsomal enzyme system reactions.

Answer 18

reduction

Question 19

what happens with warfarin in reference to phase 1 reaction??

Answer 19

Warfarin - ketone group to a hydroxyl group

Question 20

what happens with Chloramphenicol in reference to phase 1 reaction??

Answer 20

Chloramphenicol – nitro group to amine group

Question 21

________ is relying on a ‘handle’ i.e. a reactive group to form a inactive and readily excretable compound

Answer 21

Conjugation reaction

Question 22

Addition of a conjugate increases hydrophillicity

list 5 conjugates

Answer 22

Glucuronic Acid

Sulphate

Amino acids (Gly)

Glutathione (Glu-Gly-Cys)

Acetylation

Question 23

Multiple different enzymes involved

Drug metabolite should now be polar enough to be excreted via urine/faeces.

are all in which phase of metabolism

Answer 23

phase 2

Question 24

_______ is common conjugation reaction for a wide range of substrates.

Answer 24

Glucuronidation

Question 25

give an example of glucuronidation.

Answer 25

Involves transfer of activated form of glucuronic acid - paracetamol

Question 26

Many drugs undergo sequential ________and then ______________

e.g. - Aspirin - salicylic acid – glucuronide conjugate

Answer 26

phase I

phase II