Introduction of Drug Metabolism Flashcards

1
Q

What does ADME stand for?

A

Absorption
Distribution
Metabolism
Excretion

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2
Q

Stages of drug metabolism

A
Stage 1 (modification) e.g. oxidation - Hydrophobic drug
Stage 2 (Conjugation) e.g. methylation - Make drug hydrophillic 
Stage 3 (Excretion) e.g. Efflux from the cell
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3
Q

What is polymorphism?

A

Genetic changes

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4
Q

What are xenobiotics?

A

substances which are found in the body which are not naturally produced in the body

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5
Q

How is drug metabolism regulated?

A

By nuclear receptor which live in the cytoplasm of the cell

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6
Q

What is functionalisation?

A

When by phase I reaction, the functional group is exposed (e.g. -OH) so it can undergo conjugation

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7
Q

What happens during phase II drug metabolism?

A

Detoxification of drug

Gives rise to water soluble and easy to excrete products

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8
Q

Name an anti-epileptic drug

A

Phenytoin

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9
Q

Explain the functionalisation of phenytoin

A

Phenytoin (highly lipophillic) -CYP-> 4-hydroxy-phenytoin (slightly soluble in water) -UGT + UDP-GA-> 4-hydroxy-phenytoin-glucuronide (very soluble in water)

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10
Q

What is the most common form of phase I drug metabolism

A

oxidation by Cytochrome p450

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11
Q

Describe flavin-containing monooygenase (FMO)

A

A type of oxidation enzyme
Membrane bound flavin mononucleotide/ flavin adenine nucleotide containing protein
High concentrations in the liver
Subcellular location: smooth endoplasmic reticulum
Cofactors - NADPH and molecular oxygen (O2)

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12
Q

What is FMO3?

A

A gene which provides instructures to make FMO

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13
Q

Disease related to polymorphism in FMO3

A

Fish odour syndrome

  • secrete lots of TMA in urine, sweat, breath
  • severe psychological consequences
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14
Q

Describe cytochrome p450

A

Terminal oxidase in an electron transfer system of the endoplasmic reticulum

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15
Q

Functions of cytochrome p450

A
  • steroid biosynthesis
  • bile acid biosynthesis
  • xenobiotic metabolism
  • fatty acid metabolism
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16
Q

What allows the removal of an electron from NADPH?

A

p450 OxidoReductase (POR)

17
Q

POR effects

A
steroid synthesis in adrenal glands and gonads 
Cholesterol synthesis 
Metabolism in the liver of:
- steroids
- drugs 
- other xenobiotics
18
Q

What is the main type of p450 nomenculture?

19
Q

Type of anti-histamine drug

A

Terfenadine

20
Q

Type of antidepressant

A

Amitriptyline

21
Q

Describe sulphotransferases

A
Phase 2 metabolism 
Conjugating moiety: sulphate 
Location: high concentrations in the liver and intestine and also found in platelets 
Subcellular location: cytosol 
Cofactors: PAPS
22
Q

Describe N-acetyl transferases

A

Phase 2 metabolism
Conjugating moiety: acetyl group
Cofactors: acetyl CoA
Mainly in the liver and in the gut and lung

23
Q

Describe UDP-glucuronyltransferases (UGT)

A

Conjugating moiety: glucuronic acid
Membrane bound protein
High concentrations in the liver, some in the gut and other tissues
Subcellular location: smooth endoplasmic reticulum
Cofactors: UDP-GA

24
Q

Why are glucuronide good in drug metabolism?

A

They are readily excreted

25
What does the use of cytochrome p450 do to the drug?
Make electrophiles
26
What does glutathione do to the electrophiles?
Make less toxic conjugates
27
What catalysts the glutathione reaction?
Glutathione S-transferases (GST)
28
What happens to the less toxic conjugates?
Excreted in urine or bile | Metabolised further in the mercapturic acid pathway
29
Where are glutathione transferase found?
``` Cytoplasm Mitochondria Endoplasmic retriculum Nucleus In all tissues and eukaryotes ```
30
Effects of oltipraz
Inhibit phase 1 p450 enzymes and induces phase 2 enzymes
31
Effects of polymorphisms in drug metabolism
Mutations in genes for drug metabolising enzymes - leading to increased or decreased enzyme activity
32
Describe a common food-drug interaction
Bananas and ACE inhibitors - ACE inhibitors increase potassium in your body - too much potassium can cause irregular heartbeat Andy heart palpitations
33
Give the stages of drug development
1) target identification 2) target assay construction and screening 3) target validation 4) phase 1 safety 5) phase 2 efficacy safety 6) phase 3 efficacy safety 7) FDA review and approval
34
How long does drug devlopment take
12-15 years
35
Common effect of chemotherapy
Induces p450