Drug Metabolism 3

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  • Created by: LBCW0502
  • Created on: 10-02-18 10:34
What is the primary role of Phase II metabolism?
To convert the metabolite into a conjugate which can be excreted
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Why is it important to understand the Phase II reactions a potential therapeutic drug undergoes?
To understand which metabolic pathway a drug will take and how it will be excreted
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What are the consequences of saturating Phase II metabolism?
Metabolic reactions stop, leading to build up of metabolites which are difficult to excrete
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What are the types of reactions which take place during Phase II?
Sulphonation, glucuronidation, glutathione, methylation, N-acetylation, and amino acid conjunction
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What are the two major conjugation reactions in Phase II?
Glucuronidation and sulphonation (work as a pair)
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Describe features of glucuronidation
Uses UDP glucuronosyltransferases, major reaction, UGTs found in liver, UGT1/UGT2/UGT1A1. Predominantly within SER. Can occur prior to phase I activation (e.g. lorazepam/oxazepam/morphine). High capacity/unsaturable
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Where is the source of glucose for the glucuronidation reaction?
Glucose from glycolysis (steady stream - able to obtain glucose)
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Describe UDP-glycuronic acid synthesis
Glucose phosphate reacts with UTP (using pyrophosphorylase) to form UDP glucose. UDP glucose undergoes oxidation (using UDP-dehydrogenase) to form UDP-glucuronic acid (ready to be attached to molecules)
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Describe features of O-glucuronidation
Compound with OH reacts with UDP-glucuronic acid (UGT) to form O-ether glucuronide . Compound with COOH reacts with UDP-glucuronic acid to form O-ester glucuronide
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Why is an O-ester glucuronide more reactive than an O-ether glucuronide?
O-ester glucuronide contains two electronegative oxygen atoms (very reactive) attached to C. Pulls electrons away from C (partial charges on C and O). Prone to nucleophilic attack. Toxic. Phase II is detoxification (ester is an exception)
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Is it common to have multiple Phase II reactions
No (usually one reaction e.g. glucuronidation reaction occurs)
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Describe features of N-glucuronidation
Formation of aryl-n-glucuronide e.g. napthalene
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Describe features of hydroxylamine glucuronidation
Able to undergo glucuronidation on NH (OH attached to N) or on OH (OH attached to O)
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Describe features of s-glucuronidation
Glucuronide is attached to sulphur atom in the compound
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Describe features of sulphonation
Uses sulphotransferases. Found in tissues. Cytosolic enzymes. Isoforms. Excreted via urine. SULT1A1. Requires activation of sulphate using PAPS. Less capacity. Preferred method for phenols, alcohols and thyroxine
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What is the source of sulphur?
In cysteine (amino acids) found in proteins (disulfide bridges and cysteine is in the active site of P450s)
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Describe the PAPS synthesis
Sulphate ion + ATP (sulphurylase) produces APS and PPi. APS + ATP (APS phosphokinase) produces PAPS and ADP
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What is APS?
Adenosine 5'-phosphosulphate
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What is PAPS?
3'-phosphoadenosine 5'-phosphosulphate
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For sulfation reactions, do you need to specify which atom the group is attached to?
No
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Describe features of glutathione conjugation
Tripeptide (Glu-Cys-Gly), present in all cells (e.g. hepatocytes). Used to quench reactive electrophilic intermediates (recharge antioxidants e.g. vitamins E and C), presents spread of radicals in cells. Blocked synthesis results in rapid cell death
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How many different forms of glutathionesyltransferases are there?
5 - cytosolic. Compounds are stable, non-toxic, eliminated via kidney
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Describe aryl transferase activity
Remove halogen atom and add SG atoms (dehalogenation of aromatic and aliphatic compounds). G always attached to S
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Describe alkene transferase activity
Breaking a double bond (can be either aromatic or aliphatic)
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Describe epoxide transferase activity
Breaking of an epoxide bond (aromatic and aliphatic). GH added and is next to OH
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Describe the mercapturate pathway
Occurs in the kidney. Involves N-acetylation. SG to S-Cys to- S-N-acetylCys
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Describe features of N-acetylation
N-acetyltransferase. NAT1/NAT2, makes metabolite less water soluble, crystallisation in kidney (sulphonamides). Acetylation of enzyme (ping-pong mechanism), opposed to other enzymes which activate cofactor
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What is a cofactor for aromatic primary amine/sulphonamide acetylation?
Acetyl CoA
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Card 2

Front

Why is it important to understand the Phase II reactions a potential therapeutic drug undergoes?

Back

To understand which metabolic pathway a drug will take and how it will be excreted

Card 3

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What are the consequences of saturating Phase II metabolism?

Back

Preview of the front of card 3

Card 4

Front

What are the types of reactions which take place during Phase II?

Back

Preview of the front of card 4

Card 5

Front

What are the two major conjugation reactions in Phase II?

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