Drug metabolism Flashcards
What is phase 1 metabolism of drugs do in general?
Oxidation and reduction add a new functional group and hydrolysis unmasks them.
What do phase 1 metabolic reactions often make
Inactive chemicals, or prodrugs, or toxic metabolites
What different reactions are in phase 1 metabolic reactions?
Oxidation
Reduction
Hydrolysis
What does the functional group added in phase 1 metabolic reactions do?
Act as an attachment point for phase 2 reactions
What is the ‘hepatic first pass’?
All drug dose absorbed from the GI tract is first delivered to the liver by the portal vein. A fraction of the drug can then be metabolised in the liver before it reaches the systemic circulation so oral bioavailability of the drug is lower
Are xenobiotics usually lipophillic or lipophobic?
Lipophillic
What does metabolism tend to do? How?
Reduce or eliminate pharmacological activity by converting lipophilic chemicals to polar derivatives that are readily excreted
What happens to polarity of drugs after phase 1
It doesn’t change much after phase 1
What is the name of the set of enzymes that are important in phase 1
Cytochrome P450 Enzymes
Where are CYP450 enzymes predominantely found?
Liver
How many isoenzyme varieties of CYP450 are there?
57 Varieties
How do the CYP450 enzymes do their thing? What are the steps?
- Substrate binds to the gerric on the P450 enzyme
- Electron reduces the ferric
- Oxygen binds to P450 and ferrous is formed in the process
- A further reduction occurs to form a negatively charged oxygen and a ferric again (RDS)
- Ferric donates an electron to oxygen to form a very polar molecule
- O2 is then cleaved which reacts with 2 protons to form water
- Drug is then released from the system in a hydrolysed form
What step do oxidation reactions catalysed by P450 system start with (generally)
Hydroxylation step
What is the rate limiting step of the P450 enzyme reactions?
Reduction making a negatively charged oxygen and ferric
What is an aliphatic?
Straight chains of carbon atoms
What is aromatic?
Ring systems of carbon atoms
What happens in a hydroxyl oxidative reaction in phase 1?
- First reaction inactivates the pentobarbitone drug by adding an OH to the penultimate carbon
- second reaction is the activation of paracetamol from the prodrug Acetanilide by adding an OH group to the ring
What happens in a demethylation oxidative reaction in phase 1?
Methyl group removed from nitrogen or the oxygen depending on the drug
What is important to consider in a person when working out the dose of morphine to give someone?
Codeine is a prodrug that is activated by P450 enzymes and the dose would depend on how effective someones P450 enzymes are
What happens in a n-oxidative or alcohol oxidation reaction in phase 1?
Nitrogen becomes oxidised and forms a dative covalent bond with the oxygen atom (creates a very polar thus lipophilic molecule that can be excreted)
Using alcohol dehydrogenase (zero order enzyme), ethanol oxidised to acetaldehyde
What happens in reduction or hydrolysis reactions in phase 1?
Reduction breaks the molecule by adding electrons into the system
Hydrolysis then also severs the molecule into two
What is the most common reaction in phase 1?
Oxidation
What reactions take place in phase 2 metabolism?
Glucuronidation Acetylation Amino acid conjugation Sulphation Methylation Glutathione conjugation
What is special about conjugates?
They are almost always pharmacologically inactive. They are less lipid soluble and easier to excrete
What is a conjugating agent?
An agent that attaches a polar group onto the molecule in question
What is the conjugating agent and target functional group for glycuronidation?
What is formed?
UDP-glucuronic acid
-OH, -COOH, -NH2, -SH
A high energy phosphate compound is formed
What is the conjugating agent and target functional group for acetylation?
Acetyl CoA
-OH, -NH2
What is the conjugating agent and target functional group for amino acid conjugation?
Glycine, Glutamine
-COOH
What is the conjugating agent and target functional group for methylation?
S-adenosyl-methionine
-OH, -NH2
What is the conjugating agent and target functional group for sulphation?
3’-phosphoadenosine-5’-phosphosulphate
-OH, -NH2
What is the conjugating agent and target functional group for glutathione conjugation?
Glutathione
Electrophiles
Where is the acetyl group or methyl group transferred to in acetylation/methylation?
an electron rich atom
What catalyses the transfer of sulfates to substrates in sulphation?
Sulphotransferases
What is glutathioneused for in conjugation with glutathione?
To remove potentially toxic compounds
Why is drug metabolism important?
Biological half life reduced
Duration of exposure reduced
Accumulation of the compound in the body is avoided
Potency/duration of the biological activity of the chemical can be altered
The pharmacology/toxicology of the drug can be governed by its metabolism
