Drug Metabolism Flashcards
What does metabolism tend to do to a drug?
Convert drugs (usually lipid soluble) to metabolites (less lipid soluble + easier to excrete)
What is hepatic first pass metabolism?
Metabolic conversion of drug into something different before the drug enters the circulation.
In other words – the effect that occurs the very 1st time the drug passes through the liver.
What effect does extensive first pass metabolism have on bioavailability?
Extensive 1st pass metabolism -> low bioavailability
How can you avoid hepatic first pass metabolism?
Giving a drug intravenously
What are the 3 types of reaction that fall under phase I reactions?
Oxidation + Reduction (create new functional groups)
Hydrolysis (unmasks functional groups)
What is the purpose of Phase I metabolism?
Release or uncover functional groups that can be used in phase II reactions
How do phase I reactions affect polarity of the drug?
Little effect on polarity of a drug
What enzyme system is extremely important to drug metabolism? Where are these enzymes found?
Cytochrome P450
Mainly found on SER of hepatocytes in the liver
Capable of metabolising 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 at the 6 types of phase II reactions?
Glucuronidation Acetylation Sulphation Glutathione Conjugation Methylation Amino Acid Conjugation
State the conjugating agents for glutathione conjugation, glucuronidation, acetylation and sulfation
Glutathione
UDP-glucuronic acid
Acetyl CoA
3’-phosphoadenosine-5’phosphosulphate
What effect do phase II reactions have on the drugs?
Make drugs more polar + water-soluble (less lipid-soluble) so 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? When is it most likely to occur?
Glucuronidation (addition of a sugar)
Low affinity/high capacity- more likely to occur at high drug doses
What is the importance of glutathione conjugation?
Glutathione is conjugated with electrophiles so they can be excreted
Electrophiles are damaging species, often generated during metabolism – must be removed because they can cause DNA + protein damage
State an important property of the conjugates formed from glucuronidation and its impact on its excretion.
Large MW products= problem with glomerular filtration
High MW molecules are often excreted in the bile
What is the conjugating agent in acetylation and what is the product?
Acetyl CoA
Product= acetylated derivative of the drug + CoA (CoA then goes into intermediary metabolism)
What is the conjugating agent for methylation?
S-adenosyl methionine
What are the properties of the derivative formed in sulfation?
Product= sulfuric acid derivative of the drug
= very polar + water-soluble
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
Prevents accumulation of drugs in the body
Potency of biological activity can be altered
Toxicology can be governed
Why would you want a drug to be lipophilic?
So it can access tissues + have a therapeutic effect
Why would you wan a drug to be water soluble?
So it is retained in the blood + delivered to excretion sites
What is the most common Phase 1 metabolism?
Oxidation
often start with hydroxylation
What types of metabolites may be produced from Phase 1 metabolism?
Inert metabolite Active metabolite (prolongs effects) Active metabolite (prodrug)
When is sulfation most likely to occur?
Sulfation is high affinity/ low capacity
More likely to occur at low drug doses
What happens in a paracetamol OD?
Oxidation occurs to produce NAPQI (electrophile)
Electrophiles are very reactive (no issue if glutathione present)
With OD, all stores of glutathione are used up leaving very reactive phase 1 electrophile metabolite which can cause liver damage
