10 - Xenobiotic Metabolism 1 Flashcards
Why do xenobiotics require modification? (3)
To make the polar, water soluble and easier to excrete.
Give some routes of drug administration? + what is the fastest acting?
fastest - intravenous other routes: Oral subcateneous supposition intramuscular
What does ADME stand for?
Absorption, Distribution, Metabolism, Excretion
Give some factors affecting adsorption (4)
Lipohilicity, concentration gradient, ionisation, particle size
Give some routes of adsorption
Aqueous channels Transport proteins Receptor mediated endocytosis Dissolution in fats (lipophilicity) Direct passive absorption
What are the most common routes of excretion?
Renal (primary)
Biliary
Exhalation
Perspiration
What is the entero-hepatic shunt?
Recycling of xenobiotics
- Glucuronic acid conjugates excreted in bile
- The b-glucoronidase in the GIT will hydrolyse the conjugate
- Active xenobiotic is reabsorbed
What is the purpose of Phase 1 metabolism?
To create functional groups that place the xenobiotic in a correct chemical state to be acted upon at phase 2
What enzymes do the majority of phase 1 reactions employ?
Cytochrome P450 enzymes
What is glucuronidation a form of?
Conjugation
Where are cytochrome P450 enzymes found?
ER of hepatocytes, GIT, kidney
Write a monoxygenase biotransformation reaction
NADPH + H+ + O2 + SubstrateH -> NADP+ + H20 + SubstrateOH
CYP family has __% sequence homology
CYP subfamily has __% sequence homology
CYP family has 40% sequence homology
CYP subfamily has 55% sequence homology
Humans have __families and __ subfamilies of CYPs from 57 genes, CYP_ most represented
Humans have 18 families and 43 subfamilies of CYPs from 57 genes, CYP2 most represented
What leads to individual metabolic profiles (the basis of personalised medicine)
Genetic polymorphisms
What can store 2 electrons and release into the cytochrome P450 cycle?
NADPH -> FAD -> FMN
cytochrome P450 reductase
Give some cytochrome P450 oxidations (7)
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
Give 2 examples of toxic metabolites by cytochrome P450 oxidations
Benzopyrene → benzopyrene-7,8-dihydrodiol-9,10-epoxide
Paracetemol toxicity (Acetaminophen → NAPQI)
Give some oxidations not catalysed by CYPs (4)
- Alcohol dehydrogenase and aldehyde oxidation
- Xanthine oxidase
- Amine oxidases
- Flavin-containing monooxygenase system
Where are reductive reactions catalysed?
Give 2 examples
What do they require
What are they inhibited by?
Catalysed in the liver
e.g. hyrolysis and hydration
Require NADPH
inhibited by O2
What is the active metabolite of prontosil?
Sulfanilamide
In phase 1 metabolism a ___ co-factor is usually involved in the conjugation, resulting in a _____ product which can be readily _____
A high-energy co-factor is usually involved in the conjugation, resulting in a water- soluble product which can be readily excreted
What is the major acid for conjugation with carbohydrates?
What intermediate is required?
a-D-glucuronic acid
UDP-glucuronic acid intermediate required
What is metabolised by N-Glucuronidation?
amines, amides, sulfonamides
What is metabolised by O-Glucoronidation?
carboxylic acids, phenols, alcohols
What is transferred to the metabolite in Glucuronidation for increased solubility?
The glycosyl sugar of UDP-glucoronic acid
What are the 5 steps in the metabolism of codeine?
O- Dealkylation N-dealkyaltion Glucuronidation Glucuronidation N-dealkylation
What is the major metabolism pathway for phenols?
Sulfation?
Why are sulfation and glucuronidation competing pathways?
Glucuronidation at high substrate conc
Sulfation at low substrate conc
What phase 2 reaction requires acetyl CoA and takes place in the Kupffer cells in the liver.
Acetylation
Substrates include aromatic amines and sulfonamides
give the enzyme that is mainly involved in the metabolism of the following xenobiotics: Warfarin Codeine (2) Ethanol Diazepam Paracetemol
Warfarin: CYP2C9 Codeine: CYP2D6 Ethanol: CYP2E1 Diazepam: CYP3A4 and CYP2C19 Paracetemol: CYP2E1 and SYP3A4
