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.
Increase polarity and solubility so that it can more easily be excreted.
What is hepatic first pass metabolism?
Metabolic conversion of the drug in the liver, into something that is different before the drug enters the circulation.
What effect does extensive first pass metabolism have on bioavailability?
Lowers bioavailability
How can you avoid hepatic first pass metabolism?
Administer 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 (redox) or unmask (hydrolysis) functional groups that can be used in phase II reactions
How do phase I reactions affect polarity of the drug?
They have little effect on the drug polarity
What enzyme system is extremely important to drug metabolism? Where are these enzymes found?
Cytochrome P450 It is a family of 57 (Like Heinz) enzymes that are mainly found in the liver and they are capable of metabolising many xenobiotics
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.
Drug binds to iron in catalytic site of CYP450 e- donated from NADPH, reducing Fe3+ to Fe2+
Molecular oxygen binds to catalytic site, reduced into unstable form and oxidises Fe2+ to Fe3+
Second e- donated by NADPH, reducing Fe3+ to Fe2+, this FURTHER reduces Oxygen, instability leads to conversion of the drug to the hydroxylated derivative.
Reactive oxygen gains 2H+ becomes H2O
The drug is released and P450, along with its Fe3+, is ready to undergo another cycle
What is N-demethylation? What does this reaction produce?
This is the oxidation of a methyl group attached to Nitrogen, producing formaldehyde (HCHO), this removes 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 by Flavin containing monooxygenase (FMO)
Nitrogen has two free electrons that can form a dative bond with oxygen, generating an amino oxide
Describe a condition involving Flavin containing monooxygenase?
Trimethylaminuria (fish odour syndrome) is a deficiency of FMO.
Trimethylamine smells and is produced in the GI tract as a product of protein metabolism. It is converted to odourless itrimethylamine N-oxide by hepatic FMO, ready for excretion. Without FMO, Trimethylamine builds up leading to odour of ‘rotting fish’
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 in a cell, are flavin containing monooxygenase and cytochrome P450 enzymes found?
Endoplasmic Reticulum
Where in 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 and
most reductases are bacterial enzymes that are colonising our gut.
State two types of hydrolysis enzymes.
Esterases and Amidases
What at the six types of phase II reactions? What enzymes are required?
Glucuronidation - Glucuronyl Transferase
Acetylation - Acetyl Transferase
Sulphation - Sulphotransferase
Methylation - Methyl Transferase
Amino Acid Conjugation - Acyl Transferase
Glutathione Conjugation - 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
State a conjugating agent that is used for glucuronidation.
UDPGA - Uridine 5’-diphospho-glucuronosyltransferase (A Glucuronosyltransferase)
State an important property of the conjugates formed from glucuronidation and its impact on its excretion.
They are large molecular weight products so it has a problem with glomerular filtration. High molecular weight molecules are often excreted in the bile
What is the conjugating agent in acetylation and what is the product?
Acetyl Choline
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 is the conjugating agent/high energy intermediate for methylation?
S-adenosyl methionine
What effect does methylation have on polarity?
Decreases polarity (Thought that amphetamines enter this cycle by mistake because they resemble noradrenaline in structure
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, very polar
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
