Drug Metabolism Flashcards
What does metabolism tend to do to a drug?
Metabolism tends to eliminate or reduce the pharmacological and toxicological activity of a drug.
It makes the 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.
Drugs absorbed from GI tract will have to go through the liver first via portal System. A proportion of the drug will be metabolised in the liver during this process.
note that first pass metabolism refers to multiple organs that could metabolise the drug before it enters systemic circulation, but hepatic refers specifically to liver
What effect does extensive first pass metabolism have on bioavailability?
Extensive first pass metabolism -> low bioavailability
How can you avoid hepatic first pass metabolism?
Gibing 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?
Oxidation and reduction- creates new functional groups
Hydrolysis- unmasks functional groups
to introduce a ‘door handle’ ie the functional group. This functional group is then used for attachment of a polar group in phase 2 reactions
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?Where are these enzymes found?
Cytochrome P450
It is a family of 57 enzymes that are mainly found in the liver and they are capable of metabolising MOST xenobiotics
They are involved mainly in PHASE 1 OXIDATION REACTIONS
What are the substrates and products of the Cytochrome P450mediated oxidation reaction?
Substrates = drug, NADPH, oxygen (O2), protons (H+) Products = hydroxylated drug, NADP+, water
RH(drug) + NADPH + O2 + H+
–> ROH (hydroxylated drug) + NADP+ + H2O
What do P450 enzymes have in their catalytic site?
They all have a porphyrin ring and an iron group (Fe3+)
this is why he put P450-Fe3+ on slide 10
Describe the oxidation cycle of Cytochrome P450.
- The drug binds to the Fe3+ 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 electron and 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 more unstable
- Then we get conversion of the drug to the hydroxylated derivative and we lose reactive oxygen as water after the oxygen reacts with 2 protons to form H2O.
- The drug is released and P450, along with its Fe3+, is ready to undergo another cycle
THE NET RESULT:
Drug is hydroxylated by P450. Oxidation reactions generally start with a hydroxylation step that is catalysed by the P450 system
What is N-demethylation? What does this reaction produce?
This is the oxidation of a methyl group that is bound to a nitrogen
It produces formaldehyde (HCHO)
What does N-demethylation do to a drug?
It is an effective way of removing the pharmacological activity of a drug
What is O-demethylation?
Oxidative attack of P450 on a methyl group attached to oxygen
This converts oxygen to the hydroxyl group and release formaldehyde (HCHO)
What is N-oxidation? Describe the type of bond formed.
It is the oxidation of the nitrogen group itself
Nitrogen has two free electrons that can form a dative bond with oxygen
This generates an amino oxide
Which enzyme catalyses the N-oxidation reaction?
Flavin containing monooxygenase
Describe a condition involving this enzyme?
Flavin containing monooxygenase deficiency (fish odour syndrome)
Trimethylamine is produced in the GI tract as a product of proteinmetabolism Trimethylamine is foul smelling but is converted by flavin containing monooxygenase in the liver to trimethylamine N-oxide, which is odourless and can be excreted in the urine
People without flavin containing monooxygenase are unable to do this conversion so they produce trimethylamine that they can’t excrete so they end up smelling terrible
Describe alcohol oxidation.
Alcohol is first converted to acetaldehyde by alcohol dehydrogenase It is then converted from acetaldehyde to acetic acid, which is excreted
Where, within the ultrastructure of a cell, are flavin containing monooxygenase and cytochrome P450 enzymes found?
Endoplasmic reticulum
Where, within the ultrastructure of a cell, is alcohol dehydrogenase found?
Cytoplasm
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
State two types of hydrolysis enzymes.
Esterases and Amidases
What are the six types of phase II reactions?
Glucuronidation Acetylation Sulphation Methylation Amino Acid Conjugation Glutathione Conjugation
State each of the enzymes that are responsible for carrying outthese six types of phase II reactions.
Glucuronyl Transferase Acetyl Transferase Sulphotransferase Methyl Transferase Acyl Transferase Glutathione S-Transferase
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 (DNA= most electron dense thing in the body)
State a conjugating agent that is used for glucuronidation.
UDPGA
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 in acetylation and what is the product?
Acetyl CoA
The product is the acetylated derivative of the drug and CoA (CoA then goes into intermediary metabolism)
What is the conjugating agent/high energy intermediate for methylation?
S-adenosyl methionine
What effect does methylation have on polarity?
It DECREASES polarity
What is the conjugating agent used in sulphation?
PAPS – 3’-phosphoadenosine-5’-phosphosulphate
What are the properties of the derivative formed in sulphation?
The product is the sulphuric acid derivative of the drug
This is very polar and water-soluble
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
