1.7 Metabolism and Excretion Flashcards
Hepatoenteric recirculation 2) phase 1 and 2 metabolism 3) excretion
Define first pass metabolism:
occurs in the both intestine and liver before reaches systemic circulation
What is enterohepatic recirculation (HER)?
drugs that are eliminated to bile can be reabsorbed, so goes from gut to portal circulation to liver undergoes biotransformation enters bile then renters gut.
What happens to plasma concentration of a drug if HER occurs?
peaks as absorbed in gut, then on bile secretion into duodenum drug concentration increases a second time.
What sort of reactions occur in :
1) phase 1 metabolism
2) phase 2 metabolism
1) oxidation, reduction, hydrolysis, dealkylation , deamination
2) conjugation
What are the consequences of phase 1 reactions?
2)
drug can be toxic e.g. alcohol,
can make drug be in active form e.g. aspirin =salicylic acid
What are the consequences of phase 2?
2 conjugates the drug making it more water soluble
e.g. salicylic acid converted to glucuronide
1) Do all phase 1 reactions occur in liver?
1) Do all phase 1 reactions occur at ER by microsomal enzymes?
3) What do most or all drugs metabolised by and at?
1) no, e.g. hydrolytic reactions occur in plasma and other tissues
2) no, e.g. ethanol is metabolised by alcohol dehydrogenase enzyme in the cytoplasm
3) MOST (not all) , byt Cytochrome P450, a haemoprotein attached to ER.
What are the individual members of teh cytchrome P450 enzyme family refered to as ?
2) Where are they located? and amounts
3) Are CYPs always found in ER?
1) isoenzymes
2) • Main locations: intestine and liver
– Liver: hepatocytes
• Highest CYP amount in body
– Intestine: enterocytes
• Less than liver, but still significant
– Different distribution of CYPs
• Also small amounts in kidney, white blood cells, nasal passages
3) yes!
What is the important part of the structure of CYP that lets it carry out its function?
it has a haem group, important for REDOX reactions
1) Where is ethanol metabolised?
2) What is ethanol oxidised to?
1) mostly in liver
2) ethanol to acetaldehyde, then acetate
What are the ways ethanol can be converted to acetaldehyde?
- enzyme: catalase
- alcohol dehydrogenase (2/3)
- CYP2E1 (isoenzyme from CYP family)
1) What enzyme in alcohol metabolism/detoxification is most important?
2) What is the function of the enzyme?
3) Why can’t you drink alcohol if you taking metronidazole?
1) Aldehyde dehydrogenase
2) catalyses acetaldhyde to acetate
3) It inhibits the enzyme aldehyde dehydrogenase leading to accumulation of acetaldehyde
Phase 2 metabolism results in:
2) How is the conjugate excreted?
further decreases lipid solubility and almost always results in pharmacologically inactive metabolite
2) urine or bile
What is the most common conjugation reaction?
2) What mediates this reaction?
3) describe substrate specificity of this enzyme
1) glucuronidation
2) UDP-glucuronyl transferases
3) has broad substrate specificity, reaction is important for endogenous and exogenous compounds
What is the product of the detoxification reaction of aspirin
1) 60% of the time
2) 35% of the time
3) 5% of the time
b) what enzyme is important for 3)?
1) glucuronic acid
2) something with sulfiur in it
3) NAPQI then mercapuric acid
b) CYP enzymes, then glutathione S-transferase
What happens in overdose of aspirin?
2) histologically what do u see?
– Pathways of conjugation are saturated and co-factors are depleted and as such more paracetamol is metabolised via CYP450
– Toxic metabolite reacts with liver proteins instead of glutathione(depleted)
– Tissue damage occurs leading to hepatic necrosis
2) a lot more white cells less dark pink
What are the 3 main processes of renal excretion?
- Glomerular filtration
- Tubular reabsorption
- Tubular secretion
Is there a difference in excretion of lipid soluble and water soluble drugs in kidney?
2) explain?
1) yes, water soluble excreted unchanged through kidneys
2) lipid soluble, is reabsorbed on distal portion of nephron, cannot be excreted until metabolised to more polar (hydrophilic) compound
What is the max molecular weight a drug can if to be filtered out of bowman’s capsule?
20000
What affects whether a drug is filtered out in glomerular?
b) what doesn’t effect it
- molecular weight (must be less than 20000)
- concentration of FREE drug in plasma, if its bound to plasma proteins e.g. albumin , then won’t be filtered
b) lipid solubility and pH do not affect GF
How else can drug enter nephron if not by glomerular filtration?
2) Does this work for protein bound drugs?
3) What can reduce excretion if reliant on this process?
activate secretion
2) yes, as very efficient so dissociation of the drug from protein is rapid enough not to restrict the secretory process
3) competition for carriers e.g. probenecid competitively inhibit secretion of benxylpenicillin
Tubular reabsorbtion is dependent on:
- drug lipid solubility
2. pH of tubular fluid
Explain how pH of tubular fluid would effect an acidic drug excretion and alkali drug excretion if pH of tubular fluid became more alkaline:
Then an acidic drug ionises, becomes less lipid soluble. Thus its reabsorption diminishes.
But a basic drug becomes un-ionised and its reabsorption increases.
if more reabsorbtion occurs , the less it is excreted.
What type of drug would be rapidly excreted in alkaline urine?
weak acid,
