Metabolism and Excretion Flashcards
What is metabolism and excretion for?
body’s strategy for reducing exposure to potentially toxic compounds
What is xenobiotics?
chemicals foreign to body, limit bioavailibility of therapeutic drug
three main ways body protects itself?
prevent from entering blood or sensitive tissue (blood brain barrier)
physical removal from body (urine, bile, sweat)
biotransformation- products removed faster than parent compound
What is biotransformation?
increasing polarity of molecule
-decrease the lipophilicity- molecule less likely to be reabsorbed in kidney tubule or intestine
parent drug converted into a primary metabolite which may in turn act as a substrate for a second biotransformation that will produce a secondary metabolite
What do phase I reactions do?
creates a functional group or modifies an existing one- provides a chemical handle that makes metabolite more prone to undergoing a synthetic reaction
What does phase II reaction do?
coupling of metabolite with an endogenous moiety such as glucuronic acid, glutathione, sulphate etc.
now more polar and increase molecular weight
larger more charged molecules are much less likely to be reabsorbed than small, non polar ones
What does biotransformation do to product compound?
activity reduced compared to parent compound
What enzymes facilitate phase I?
CP450 and short chain dehydrogenases
Does parent drug need to undergo phase I reaction?
no, depends on chemical structure of parent drug
Creation of functional groups?
oxidation reaction- CP450
also reductases and hydrolytic enzymes
modification reactions?
hydrolysis- esterases and amidases
What do chemically functional groups include?
Hydroxyl, amino and thiol
Where do phase I reactions happen?
liver
gut, small intestine, lung and kidney
IN CELL: smooth endoplasmic reticulum
-some in mitochondria
-cytosol
What intermediates are toxic?
intermediates like quinones and quinone analogues
Why are some intermediates toxic?
- Some of the intermediates are highly electrophilic
- Can covalently modify macromolecules (adducts; proteins and DNA)
- Bioactivation
Why would a drug be given in an inactive (or less active) form (pro-drug)?
useful in overcoming absorption and distribution issues
improve safety if active drug would cause problems at site of administration
due to unpleasant organoleptic (effect on senses) properties of the active drug
Give characteristics of CP450?
some have broad substrate specificty (3A4) , others not
many polymorphic variants of some of cytochrome P450s (variation in gene sequence can have a big impact on activity when it comes to drug metabolism)
mono-oxygenases -most common catalysed reaction is the addition of a single atom of oxygen into an organic substrate
Where do phase 2 reactions happen?
within liver, hepatocytes
extrahepatic too
Give characteristics of phase II?
products are larger, more hydrophillic and are therefore more likely to be excreted
are also almost invariably less pharmacologically active
the products tend to be weak acids -at most physiological pH they will be largely ionised and therefore less likely to be reabsorbed
these conjugates more likely to bind to plasma proteins - which reduces the likelihood of their distribution to other tissues
availibility of cofactors that determine capacity of reaction
what happens when overdose of paracetamol?
excess NAPQI accumulates with resulting liver damage
What is N -acetyl cysteine for?
sulphydryl containing drug that breaks down the mucus that causes problem in the gut and resp tract in cystic fibrosis
Why is N-acetyl cysteine an antidote for paracetomol overdose?
replenishes glutathione and enhances activity of glutathione -S-transferase (enzyme that catalyses the conjugation reaction)
What cycloprotein is important for increasing toxicity of paracetomol?
CYP2E1- if induced paracetomol toxicity is more likely
What things might induce CYP2E1?
St John’s wort herbal medicine
What does omeprazole inhibit?
CYP3A4
What does grapefruit juice inhibit?
CYP3A4
What are the two pathways of the coagulation cascade and where do they converge?
extrinsic - activated in response to trauma- which damages blood vessels
Intrinsic- triggered by endothelial damage and the exposure of underlying matrix proteins
converge- at the end
What is warfarin?
powerful anti-coagulant that acts by blocking this vitamin K recycling (vitamin K carboxylates enzymes which activates the enzymes)
What metabolises warfarin ?
CYP2C9
What is elimination and what does it encompass?
final -metabolism and excretion
What is excretion?
rate at which drug is removed from body
What is clearance?
the volume of plasma from which the drug would be totally removed per unit time
How does plasma conc relate to clearance?
higher the plasma concentration, higher the clearance
what are the factors that affect drug concentration in plasma?
clearance (if clearance high-increased dose and if clearance low- less drug) and bioavailibility
What is total clearance?
renal + hepatic + lung etc.
What 3 things make clearance?
glomerular filtration
tubular secretion
reabsorption
What is needed for a drug to be filtered in the kidney?
firstly be present in plasma
and free (depend on volume of distribution and extent of plasma protein binding)
size and charge
What does clearance depend on?
perfusion and health of the kidney - esp glomerulus
What is the amount of drug cleared by filtration equal to?
fraction unbound x glomelular filtration rate
What is active renal secretion?
mainly occurs in proximal tubule
weak acid or base transporters, nucleoside transporters and p-glycoprotein transporters
can clear drugs too large to filter
depends on blood flow, free drug
saturable
if renal clearance exceeds GFR, likely been actively secreted in this way
What is passive tubular reabsorption?
Lipid solubility
* Concentration gradient
* Dehydration (highly concentrated
urine = highly concentrated drug)!
* Depends on urine flow rate
* But also pH
* Back to ion trapping again!
* Urinary alkalisation can be used to
increase clearance of weak acids
* (Aspirin
What is renal clearance proportional to?
GFR
Give characteristics of hepatic clearance?
- Perfusion important here, too (also
needs to be free drug) - Also dependent on the efficiency of
removal of drug from the blood - (Hepatic extraction ratio)
- Hepatic clearance = hepatic blood flow x
hepatic extraction ratio - Intrinsic clearance capacity- enzymes and transporters
- High intrinsic clearance capacity: clearance is perfusion limited
Enterohepatic recirculation?
- Conjugates excreted in the bile are
polar - Poorly reabsorbed
- Enzymes expressed by gut
microbiota - “de-conjugate”
- Secondary drug absorption
- Prolonging drug action
- Antibiotics, opioids, warfarin etc
- Combined oral contraceptives
