1.7 Metabolism and Excretion

Question 1

Define first pass metabolism:

Answer 1

occurs in the both intestine and liver before reaches systemic circulation

Question 2

What is enterohepatic recirculation (HER)?

Answer 2

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.

Question 3

What happens to plasma concentration of a drug if HER occurs?

Answer 3

peaks as absorbed in gut, then on bile secretion into duodenum drug concentration increases a second time.

Question 4

What sort of reactions occur in :

1) phase 1 metabolism
2) phase 2 metabolism

Answer 4

1) oxidation, reduction, hydrolysis, dealkylation , deamination
2) conjugation

Question 5

What are the consequences of phase 1 reactions?

2)

Answer 5

drug can be toxic e.g. alcohol,

can make drug be in active form e.g. aspirin =salicylic acid

Question 6

What are the consequences of phase 2?

Answer 6

2 conjugates the drug making it more water soluble

e.g. salicylic acid converted to glucuronide

Question 7

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?

Answer 7

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.

Question 8

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?

Answer 8

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!

Question 9

What is the important part of the structure of CYP that lets it carry out its function?

Answer 9

it has a haem group, important for REDOX reactions

Question 10

1) Where is ethanol metabolised?

2) What is ethanol oxidised to?

Answer 10

1) mostly in liver

2) ethanol to acetaldehyde, then acetate

Question 11

What are the ways ethanol can be converted to acetaldehyde?

Answer 11

1. enzyme: catalase
2. alcohol dehydrogenase (2/3)
3. CYP2E1 (isoenzyme from CYP family)

Question 12

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?

Answer 12

1) Aldehyde dehydrogenase
2) catalyses acetaldhyde to acetate
3) It inhibits the enzyme aldehyde dehydrogenase leading to accumulation of acetaldehyde

Question 13

Phase 2 metabolism results in:

2) How is the conjugate excreted?

Answer 13

further decreases lipid solubility and almost always results in pharmacologically inactive metabolite
2) urine or bile

Question 14

What is the most common conjugation reaction?

2) What mediates this reaction?
3) describe substrate specificity of this enzyme

Answer 14

1) glucuronidation
2) UDP-glucuronyl transferases
3) has broad substrate specificity, reaction is important for endogenous and exogenous compounds

Question 15

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)?

Answer 15

1) glucuronic acid
2) something with sulfiur in it
3) NAPQI then mercapuric acid
b) CYP enzymes, then glutathione S-transferase

Question 16

What happens in overdose of aspirin?

2) histologically what do u see?

Answer 16

– 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

Question 17

What are the 3 main processes of renal excretion?

Answer 17

1. Glomerular filtration
2. Tubular reabsorption
3. Tubular secretion

Question 18

Is there a difference in excretion of lipid soluble and water soluble drugs in kidney?
2) explain?

Answer 18

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

Question 19

What is the max molecular weight a drug can if to be filtered out of bowman’s capsule?

Answer 19

20000

Question 20

What affects whether a drug is filtered out in glomerular?

b) what doesn’t effect it

Answer 20

1. molecular weight (must be less than 20000)
2. 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

Question 21

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?

Answer 21

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

Question 22

Tubular reabsorbtion is dependent on:

Answer 22

1. drug lipid solubility

2. pH of tubular fluid

Question 23

Explain how pH of tubular fluid would effect an acidic drug excretion and alkali drug excretion if pH of tubular fluid became more alkaline:

Answer 23

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.

Question 24

What type of drug would be rapidly excreted in alkaline urine?

Answer 24

weak acid,

Question 25

What type of drug would be rapidly excreted in acid urine?

Answer 25

weak base

Question 26

How are volatile drugs removed from the bodt?

Answer 26

Volatile gases are eliminated by exhalation

Question 27

How are water-soluble and lipid soluble drugs excreted?

Answer 27

Water-soluble compounds are often eliminated to some degree unchanged in the urine
• Also may be excreted in the bile – Lipid-soluble compounds typically undergo metabolism to more watersoluble metabolites that are then excreted in the urine and/or bile

Question 28

Is water soluble or lipid soluble drugs gonna be reabsorbed in the nephron?

Answer 28

lipid soluble, reducing their renal excretion

Question 29

What is used as a measure of the ability of the eliminating organs to remove a compound from the body ?

2) How is it calculated?
2b) How else can it be calculated?
3) What cann it be defined as?

Answer 29

1) Clearance
2) Total CL = Hepatic CL + Renal CL + all other CL
2b) Elimination rate constant (q) * volume of distribution
2c) Cl= dose/AUC
3) May be defined as the volume of plasma (or blood) cleared of the compound per unit of time (typically expressed as L/hr in clinical pharmacokinetics, but can be any volume/time)

Question 30

How can volume o distribution be calculated using a graph of x= time, and y= plasma conc.?

Answer 30

Vd= dose/ C0
C0= extrapolate graph back is they y intercept

Question 31

How do you find the half life of a drug?

2) how many halfs are needed to completely remove drug from body?

Answer 31

it is the time taken for 50% decrease in conc. plasma,

2) 5 half lifes

Question 32

How does ethanol effect metabolism of paracetamol:

2) Which pathway is encouraged?

Answer 32

CYP450 metabolism to a toxic metabolite enhanced by ethanol consumption
2) paracetamol to NAPQI to mercapturic acid

Question 33

Are CYPs ever inhibited?

Answer 33

yes, sometimes for the benefit of reduced rate of metabolism meaning increased pharmacological effect