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Metabolism in H&D > 10 - Xenobiotic Metabolism 1 > Flashcards

10 - Xenobiotic Metabolism 1 Flashcards

1
Q

Why do xenobiotics require modification? (3)

A

To make the polar, water soluble and easier to excrete.

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2
Q

Give some routes of drug administration? + what is the fastest acting?

A 
fastest - intravenous
other routes: Oral
subcateneous
supposition
intramuscular
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3
Q

What does ADME stand for?

A

Absorption, Distribution, Metabolism, Excretion

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4
Q

Give some factors affecting adsorption (4)

A

Lipohilicity, concentration gradient, ionisation, particle size

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5
Q

Give some routes of adsorption

A 
Aqueous channels
Transport proteins
Receptor mediated endocytosis
Dissolution in fats (lipophilicity)
Direct passive absorption
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6
Q

What are the most common routes of excretion?

A

Renal (primary)
Biliary
Exhalation
Perspiration

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7
Q

What is the entero-hepatic shunt?

A

Recycling of xenobiotics

  • Glucuronic acid conjugates excreted in bile
  • The b-glucoronidase in the GIT will hydrolyse the conjugate
  • Active xenobiotic is reabsorbed
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8
Q

What is the purpose of Phase 1 metabolism?

A

To create functional groups that place the xenobiotic in a correct chemical state to be acted upon at phase 2

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9
Q

What enzymes do the majority of phase 1 reactions employ?

A

Cytochrome P450 enzymes

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10
Q

What is glucuronidation a form of?

A

Conjugation

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11
Q

Where are cytochrome P450 enzymes found?

A

ER of hepatocytes, GIT, kidney

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12
Q

Write a monoxygenase biotransformation reaction

A

NADPH + H+ + O2 + SubstrateH -> NADP+ + H20 + SubstrateOH

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13
Q

CYP family has __% sequence homology

CYP subfamily has __% sequence homology

A

CYP family has 40% sequence homology

CYP subfamily has 55% sequence homology

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14
Q

Humans have __families and __ subfamilies of CYPs from 57 genes, CYP_ most represented

A

Humans have 18 families and 43 subfamilies of CYPs from 57 genes, CYP2 most represented

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15
Q

What leads to individual metabolic profiles (the basis of personalised medicine)

A

Genetic polymorphisms

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16
Q

What can store 2 electrons and release into the cytochrome P450 cycle?

A

NADPH -> FAD -> FMN

cytochrome P450 reductase

17
Q

Give some cytochrome P450 oxidations (7)

A

Epoxidation (benzopyrene)
N-oxidation (nitrogen heterocycles)
Hydroxylation (aromatic/aliphatic amines)
S-oxidation (chlorpromazine [antipsyctotic])
N- and O-, dealkylation (diazepam, codeine)
Oxidative dehalogenation (halothane)
CYP2E1 oxidation of ethanol

18
Q

Give 2 examples of toxic metabolites by cytochrome P450 oxidations

A

Benzopyrene → benzopyrene-7,8-dihydrodiol-9,10-epoxide

Paracetemol toxicity (Acetaminophen → NAPQI)

19
Q

Give some oxidations not catalysed by CYPs (4)

A
  • Alcohol dehydrogenase and aldehyde oxidation
  • Xanthine oxidase
  • Amine oxidases
  • Flavin-containing monooxygenase system
20
Q

Where are reductive reactions catalysed?
Give 2 examples
What do they require
What are they inhibited by?

A

Catalysed in the liver
e.g. hyrolysis and hydration
Require NADPH
inhibited by O2

21
Q

What is the active metabolite of prontosil?

A

Sulfanilamide

22
Q

In phase 1 metabolism a ___ co-factor is usually involved in the conjugation, resulting in a _____ product which can be readily _____

A

A high-energy co-factor is usually involved in the conjugation, resulting in a water- soluble product which can be readily excreted

23
Q

What is the major acid for conjugation with carbohydrates?

What intermediate is required?

A

a-D-glucuronic acid

UDP-glucuronic acid intermediate required

24
Q

What is metabolised by N-Glucuronidation?

A

amines, amides, sulfonamides

25
Q

What is metabolised by O-Glucoronidation?

A

carboxylic acids, phenols, alcohols

26
Q

What is transferred to the metabolite in Glucuronidation for increased solubility?

A

The glycosyl sugar of UDP-glucoronic acid

27
Q

What are the 5 steps in the metabolism of codeine?

A 
O- Dealkylation
N-dealkyaltion
Glucuronidation
Glucuronidation
N-dealkylation
28
Q

What is the major metabolism pathway for phenols?

A

Sulfation?

29
Q

Why are sulfation and glucuronidation competing pathways?

A

Glucuronidation at high substrate conc

Sulfation at low substrate conc

30
Q

What phase 2 reaction requires acetyl CoA and takes place in the Kupffer cells in the liver.

A

Acetylation

Substrates include aromatic amines and sulfonamides

31
Q 
give the enzyme that is mainly involved in the metabolism of the following xenobiotics:
Warfarin
Codeine (2)
Ethanol
Diazepam
Paracetemol
A 
Warfarin: CYP2C9
Codeine: CYP2D6
Ethanol: CYP2E1
Diazepam: CYP3A4 and CYP2C19
Paracetemol: CYP2E1 and SYP3A4

Metabolism in H&D (14 decks)

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