Drug Metabolism Flashcards
What does metabolism tend to do to a drug?
- reduce the pharmacological and toxicological activity of a drug.
- more polar and soluble so that it can more easily be excreted.
What is hepatic first pass metabolism?
Metabolic conversion of the drug into something that is different before the drug enters the circulation.
In other words – the effect that occurs the very first time the drug passes through the liver.
Make the drug more water soluble to be excreted
What effect does extensive first pass metabolism have on bioavailability?
Extensive first pass metabolism -> low bioavailability
How can you avoid hepatic first pass metabolism?
Giving a drug intravenously
What are the three types of reaction that fall under phase I reactions?
Oxidation
Reduction
Hydrolysis
What is the purpose of Phase I metabolism?
It is meant to release or unmask functional groups that can be used in phase II reactions as a point of attachment
How do phase I reactions affect polarity of the drug?
They have little effect on the polarity of a drug
What enzyme system is extremely important to drug metabolism?
Cytochrome P450
What are the substrates and products of the Cytochrome P450 mediated oxidation reaction?
Substrates = drug, NADPH, oxygen (O2), protons (H+) Products = hydroxylated drug, NADP+, water
What do P450 enzymes have in their catalytic site?
They all have a porphyrin ring and an iron group (Fe3+)
Describe the oxidation cycle of Cytochrome P450.
The drug binds to the iron in the catalytic site of CYP450 An electron is fed in from NADPH, which is picked up by the Fe3+ making it Fe2+
Then molecular oxygen binds to the catalytic site and Fe2+ loses its electron to become Fe3+ again, and oxygen picks up the extra electronand becomes unstable
Then a second electron is donated by NADPH, which, again, reduces Fe3+ to Fe2+ Fe2+ then donates this electron to the already unstable oxygen to make it even less stable
Then we get conversion of the drug to the hydroxylated derivative and we lose reactive oxygen as water with the uptake of two protons
The drug is released and P450, along with its Fe3+, is ready to undergo another cycle
Where do reduction reactions tend to take place within the body and why?
GI tract because this is a low oxygen environment
Most reductases are bacterial enzymes that are colonising our gut, which is why these tend to happen in the GI tract
What effect do phase II reactions have on the drugs?
They make drugs more polar and water-soluble (less lipid-soluble) so that they can be excreted more easily
What are some features of conjugating agents?
Large
Polar
Endogenous
What is the most common type of phase II reaction?
Glucuronidation (addition of a sugar to a molecule)
What is the importance of glutathione conjugation?
Glutathione is conjugated with electrophiles so that they can be excreted
Electrophiles are damaging species that are often generated during metabolism – they must be removed because they can cause DNA and protein damage
State an important property of the conjugates formed fromglucuronidation and its impact on its excretion.
They are large molecular weight products so it has a problem withglomerular filtration
High molecular weight molecules are often excreted in the bile
What is the conjugating agent used in sulphation?
PAPS – 3’-phosphoadenosine-5’-phosphosulphate
What type of molecule is glutathione?
Tripeptide consisting of:
Glycine
Glutamine
Cysteine
What effect does drug metabolism have on biological half-life, duration of exposure and accumulation of drugs in the body?
Decreases biological half-life
Decreases duration of exposure
Avoids accumulation of drugs in the body
What compounds are formed by oxidation reactions
Electrophiles
What types of compounds are formed from reduction and hydrolysis
Nucleophiles
Conjugating agent for acetylation
Acetyl CoA
Metabolism of paracetamol
50% sulfation as high affinity
30% Glucuronidation as low affinity
20% glutathionine conjugation
Amino acids used in conjugation
Glycine
Glutamine
Taurine
Conjugating agent for methylation
S-adenosyl-methionine
Other Phase 2 reactions
Methylation
Amino acid conjugations
What to give in paracetamol overdose
IV n-acetylcysteine
Glutathionine conjugation of paracetamol
Phase 1 oxidation produces reactive intermediate NAPQI via Cyt P450
This electrophiles can then be detoxified by glutathionine conjugation
Conjugating agent for sulfation
3-phosphoadenosine-5-phosphosulphate
Conjugating agent for glucuronidation
UDP glucuronic acid
Phase 2 reactions for nucleophiles
Glucuronidation
Acetylation
Sulfation
Conjugating agent for glutathionine
Glutathionine
Phase 2 reaction on electrophiles
Glutathionine conjugation
