drug metabolism reactions

Question 1

why do we need to know about elimination?

Answer 1

Main goal of the therapy is to achieve certain therapeutic level for a certain period time of time but then for it to be able to leave the body.
You need to know how quickly it is eliminated so you know what conc will be in the plasma and for how long.

Question 2

what are the major sites of metabolism?

Answer 2

liver and intestine

Question 3

what is metabolism?

Answer 3

 Involves enzymatic conversion of a drug to metabolites. Changing structure of the molecule as you introduce other functional groups therefore changing the properties of the molecule.
 Metabolites are more polar and hydrophilic than the parent drug and are renally excreted
 Prevents drug accumulation

Question 4

what are the main sites of excretion?

Answer 4

 Liver (biliary excretion) when you have excretion from pile
 Lungs (pulmonary) if you have inhaled molecules

Question 5

what is excretion?

Answer 5

 Elimination of unchanged drug or its metabolites from the body
 Has not undergone any metabolic conversions
 Occurs mostly in the kidney often excreted from urine

Question 6

what is the importance of drug metabolism?

Answer 6

 Metabolites are generally pharmacologically inactive and less toxic than the parent

Question 7

what are the exceptions of drug metabolites?

Answer 7

• pharmacologically active
• reactice TOXIC
• prodrugs

Question 8

what are drug metabolising enzymes?

Answer 8

• very broad substrate specificity
• localisation
• ubiquitous enzymes

Question 9

what is the role of liver in drug metabolism and elimination”?

Answer 9

 Most important due to size, blood flow and high enzyme concentration in hepatocytes
 Phase I (cytochrome P450s) and phase II enzymes (e.g., UGT – glucuronidation)
 Some drugs eliminated unchanged via biliary excretion (e.g. pravastatin).
 Anatomical position - extensive first-pass metabolism
 Infrastructure and subcellular localisation of enzymes (endoplasmic reticulum/microsomes)

Question 10

what are examples of pharmacologically active metabolites?

Answer 10

: ezetimibe(active metabolite) glucuronide, morphine 6-glucuronide – unique of often due to them being very polar they don’t usually have pharmacological activity but it is more common with phase 1 metabolites.

Question 11

what is the plasma conc of metabolites like?

Answer 11

can be greater than the parent drug. you need to understand its properties to be able to understand

Question 12

what are the comparisons of lipophilicty in parent drug to metabolite?

Answer 12

Parent = high
metabolite = low

Question 13

what are the comparisons of water solubility in parent drug to metabolite?

Answer 13

parent = low
metabolite = high

Question 14

what are the comparisons of pKa acidic in parent drug to metabolite?

Answer 14

parent = >5
metabolite = strong acids

Question 15

what are the comparisons of pKa basic in parent drug to metabolite?

Answer 15

parent = <9

Question 16

what are the comparisons of renal clearance in parent drug to metabolite?

Answer 16

parent = low
metabolite = high

Question 17

what are examples of metabolites which can inhibit metabolic enzymes?

Answer 17

(gemfibrozil glucuronide, itraconazole metabolites, all cause inhibitio

Question 18

how do you use the endoplasmic reticulum to study drug metabolism in vitro?

Answer 18

 Centrifuged sequentially (differential centrifugation) to give microsomes
 Most oxidation enzymes (Cytochrome P450) are membrane bound and located in microsomes
 Microsomes from human liver, intestine and kidney widely used in drug development
 recombinant enzymes (one enzyme in isolation), hepatocytes (cells bought commercially), liver chip (mimic physiological conditions and you have a flow) also used –
 This is because the liver is more homogenous compared to kidney

Question 19

what are the different types of drug metabolism reactions?”

Answer 19

1. oxidation
2. reduction
3. hydrolysis
4. conjugation

Question 20

what are phase 1 reactions?

Answer 20

oxidation, reduction and hydrolysis

Question 21

what are phase 2 reactions?

Answer 21

conjugation

Question 22

which the most important type of drug metabolism reaction/

Answer 22

Oxidation is the most important
 Catalysed by a super-family of enzymes - Cytochrome P450s*
 Many new developing drugs metabolised by direct conjugation

Question 23

what is an example of phase 1 and phase 2 reaction?

Answer 23

phase 1 is the initial phase when you introduce a certain group
Phase 2 sugests reaction occurs after phase1 and this is usually a conjugation to produce a metabolite.
not all molecules need to go through phase 1

Question 24

explain what a phase 1 reaction is?

Answer 24

• introduce or expose a functional group (changes the chemical structure as a result)
• oxidation occurs at C, N or S
•  C hydroxylations: aromatic or aliphatic Cs
   Cleavage: loss of alkyl or amino group (N-, O-, S-dealkylation)
   N and S oxidations
   Reduction - acts on nitro and keto groups
• hydrolysis of esters or amide groups

Question 25

what is an example of a phase 1 metabolic reaction?

Answer 25

1. aromatic oxidation - results in formation of phenols

2. aliphatic oxidation - results in the formation of alcohols

Question 26

what are other forms of oxidative cleavage reactions?

Answer 26

• deamination
• desulphuration
• dechlorination

Question 27

what are non oxidation metabolic rections?

Answer 27

• reduction –> liver enzymes but mainly by gut microflora which can differ between indivuduals and cause variations
• hydrolysis

Question 28

what is parallel metabolism?

Answer 28

competing reaction

Question 29

what is a molecule that undergoes parallel reactions?

Answer 29

Paracetamol is the parent moeucles and this can either undergo phase, or direct conjugation of parent molecule.
3 process occur in parallel from parent. Direct conjugation is dominant – this is different to sequential metabolism. All occur on the parent molecule. The red to purple route is a example of sequential but the rest are parallel