Drug metabolism reactions - elimination

Question 1

What is elimination?

Answer 1

• Metabolism + excretion (2 mechanisms)

- It is the irreversible removal or loss of a drug from the body

Question 2

Where does metabolism predominantly occur?

Answer 2

Liver and some in the intestine

Question 3

What is the dominant mechanism of elimination?

Answer 3

metabolism

Question 4

What happens during metabolism?

Answer 4

• Involves a chemical reaction - change in structure of molecule, changing functional groups and therefore properties
• Conversion to metabolites

Question 5

What properties do metabolites have?

Answer 5

They are more polar and hydrophilic than the parent molecule, this prevents drug accumulation.

Question 6

What is excretion?

Answer 6

Elimination of unchanged drug or its metabolites from the body

Question 7

Where does excretion occur?

Answer 7

Mostly in the kidney - via urine, although can occur in the liver (biliary excretion via efflux transporters and into faeces) and in the lungs (pulmonary, for inhaled molecules)

Question 8

Are metabolites that are formed generally active or inactive?

Answer 8

Generally inactive and LESS toxic than the parent molecule

Question 9

What drugs show exceptions to the usually inactive metabolite?

Answer 9

Prodrugs - inactive or weakly active drug that produces active metabolite e.g. levodopa –> dopamine (conversion is necessary to form the active drug)

Question 10

What is the most common cause of DDIs?

Answer 10

Inhibition of metabolic enzymes in the liver/intestine

Question 11

What properties of metabolites facilitate elimination?

Answer 11

• Low lipophilicity
• high water solubility
• strong acids

Question 12

Do metabolites have a therapeutic value?

Answer 12

No, they are not pharmacologically active.

However, there are some exceptions: ezetimibe glucuronide, morphine 6-glucuronide

Question 13

What can some metabolites do that contributes to DDIs?

Answer 13

Inhibit metabolic enzymes and transporters (gemfibrozil glucuronide, itraconazole metabolites)

Question 14

Why is the liver the most important for metabolism and elimination?

Answer 14

• Large in size
• Dual blood flow from portal vein and hepatic artery
• High enzyme concentration in hepatocytes

Question 15

What do liver cells have high expression of?

Answer 15

Phase 1 enzymes (CYP450s) and phase 2 enzymes (e.g. UGT - glucuronidation)

Question 16

What subcellular fractions in the liver are used for studying drug metabolism in vitro?

Answer 16

Enzymes placed in the membrane of the endoplasmic reticulum (broken up by homogenisation).
- they are centrifuged sequantially to give microsomes

Question 17

Where are most oxidation enzymes found?

Answer 17

(CYP450s) are membrane bound and located in microsomes

Question 18

What are the 4 drug metabolism reactions?

Answer 18

1. Oxidation
2. Reduction
3. Hydrolysis
4. Conjugation

• 1-3: phase 1 reactions
  4: phase 2 reaction

Question 19

What is the most important metabolic reaction?

Answer 19

Oxidation:

• catalysed by a super family of enzymes (CYP450s)
• many new developing drugs are metabolised by direct conjugation

Question 20

Describe a common phase 1 reaction?

Answer 20

Parent molecule: undergoes an initial reaction (often oxidation) and a certain functional group is introduced - therefore changing the chemical structure of the molecule

Question 21

Describe a phase 2 reaction?

Answer 21

Sequential metabolism (often conjugation reactions)

Question 22

Where does oxidation occur on a molecule?

Answer 22

At C, N or S atoms

Question 23

What are the 3 types of oxidation reactions?

Answer 23

o C hydroxylation: aromatic or aliphatic Cs
o Cleavage: loss of alkyl or amino group (N-,O-,S-dealkylation)
o N and S oxidations

Question 24

Where does reduction occur?

Answer 24

Acts on nitro and keto groups

Question 25

Where does hydrolysis occur?

Answer 25

Acts on ester and amide groups

Question 26

What are the 3 oxidation reactions at carbon?

Answer 26

• Aromatic (hydoxylation)
• Aliphatic (hydroxylation)
• De-alkylation (oxidative cleavage)

*2 apparent different mechanisms: hydroxylation and oxidative cleavage

Question 27

What does aromatic oxidation result in the formation of?

Answer 27

PHENOLS:

- addition of OH group to aromatic ring (hydroxylation)

Question 28

What does aliphatic oxidation result in the formation of?

Answer 28

ALCOHOLS

Question 29

What type of oxidation is de-alkylation?

Answer 29

Oxidative cleavage

Question 30

What are the 2 types of de-alkylation?

Answer 30

a) O-dealkylation – results in formation of phenols – codeine (eliminate methyl group)
b) N-dealkylation – results in formation of amines (again, eliminate methyl groups)

Question 31

What are other types of oxidative cleavage reactions?

Answer 31

o Deamination
o Desulphuration
o Dichlorination

(all involve initial carbon oxidation)

Question 32

What contributes to reduction reactions?

Answer 32

Liver enzymes and gut microflora

Question 33

What groups can be targeted to form a primary amine?

Answer 33

a) nitro group (NO2)
b) azo group (N=N)
c) keto group (C=O)*?

Question 34

What are the 2 types of hydrolysis reactions?

Answer 34

Ester and amide hydrolysis

Question 35

What are hydrolysis reactions catalysed by?

Answer 35

carboxylesterases (expressed in liver and intestine)

Question 36

Where does sequential oxidation occur?

Answer 36

• Sequential oxidation on the same C (CH2OH–>COOH)

* Sequential oxidation on a different C (E.g. hydroxylation of a demethylated metabolite)

Question 37

What is parallel metabolism?

Answer 37

• Competing reactions
• Can undergo phase 1 CYP450 reactions
• direct conjugation can also occur as well as direct sulphonation
• all happen in parallel