Pharmacokinetics: Metabolism and Excretion

Question 1

Where does drug metabolism happen at tissue level?

Answer 1

1. Liver for foreign bodies and particles
2. Kidneys acting as a filter
3. Lungs for the volatile anaesthetics

Question 2

Where does drug metabolism happen at intracellular level?

Answer 2

1. Mitochondria- cell organelle involved in producing ATP

2. Smooth Endoplasmic reticulum

Question 3

What properties can change when the parent compound metabolises into the metabolite?

Answer 3

1. Increase in water solubility
2. Decrease in biological activity
3. Increase in biological activity- need to consider the concentration
4. Change in the nature of the biological activity

Question 4

What is the phase 1 reaction of metabolism?

Answer 4

1. Preparing the molecule that expose function groups

2. Different conjugative entities that are added to the drug

Question 5

What is the 3 main chemical reactions that the drug structure must go under to prepare it for the conjugative step itself?

Answer 5

1. Oxidation
2. Reduction
3. Hydrolysis

Question 6

What are cytochrome P450, where are they located and what is its role?

Answer 6

1. 20 Isoenzymes that are located in the smooth ER

2. which are very diverse to metabolise different compounds (any foreign bodies)

Question 7

Explain the how a molecule interacts with cytochrome P450?

Answer 7

1. Molecule interacts with cytochrome P450 to get oxidised

2. 1 to 4 family groups of cytochrome P450 are involved in drug metabolism

Question 8

How does the phase 2 reaction of metabolism work?

Answer 8

1. Involves the formation of a covalent bond
2. Results in a H2O soluble conjugate (excretion)
3. Products are predominantly INACTIVE (to remain excreted), but in some cases the activity remains

Question 9

How does codeine work when metabolised?

Answer 9

1. Codeine is metabolised to morphine and then to Morphine-6-glucuronide
2. Leads to increase of analgesic effect through opioid receptor agonist profile

Question 10

What is 1st pass metabolism? And give examples of where it happens?

Answer 10

1. When the metabolism begins before the drug reaches general circulation

2. Examples of where it happens:
Liver
Lung 
Intestinal lumen
Intestinal wall

Question 11

What are the two factor that affect metabolism and give two examples of them?

Answer 11

1. Genetic influences
   - Example: different races turn a different percentage of codeine into morphine
   - Some are poor, intermediate, ultra rapid, and extensive
2. External factors
   Example: grape fruit inhibits the enzymes CYP3A4 and CYP1A2 and this reduces the first pass effect of drugs
   - Drugs are metabolised by enzymes in the guy wall
   - Increases concentration in the plasma
   - Doesn’t affect IV drugs

Question 12

What are the various routes of excretions in fluids, solids and gases?

Answer 12

Fluids: Important for low MW compounds

• urine
• bile
• sweat
• tears
• breast milk

Solids: Important for high MW compounds

• Faeces
• Hair

Gases (expired air): important for volatile compounds

Question 13

Where are compounds excreted in the renal system?

Answer 13

1. Glomerular
2. Reabsorption
3. Tubular Excretion- distal tubular end

Question 14

What is glomerular filtration?

Answer 14

1. Blood flow through the glomerulus filtering the compound through the blood stream itself
2. Allow passage if 20kDa molecules or below
3. Occurs under hydrostatic pressure
4. Contains about 20% of the plasma volume delivered

Question 15

How does tubular secretion work?

Answer 15

1. Renal tubule has secretory transporters on both basolateral and apical membranes
2. They can transport acidic (organic anion transporters) or basic compounds (organic cation transporters)
3. Lead to a rate of rapid decrease in plasma concentration of unbound drug which causes a rapid dissociation of any drugs bound to proteins in the plasma

Question 16

How does reabsorption work and how do drugs affect this?

Answer 16

1. Body wants to retain some constituents of the glomerular filtrate
2. Uptake processes exist for carbohydrates and amino acids
3. Tubule can pass back into the plasma
4. Drugs can hijack the system as substrates for the uptake processes

Question 17

Where is the enterohepatic cycling located and what is it?

Answer 17

1. Engineered within the liver and bile ducts with glucuronic acid
2. Where by the drug conjugates and it’s too polar (ionised)
3. Remains in the gut and is broken down by enzymes releasing the parent molecule
4. parent molecule is reabsorbed and then used again

Question 18

How does enterohepatic cycling help certain drugs? Give example of the drugs?

Answer 18

Goes through the cycle which helps the drug maintain a high plasma concentration by not allowing it to break down

Examples:

• Ethinylestradiol (oral contraceptives)
• Morphine

Question 19

What are the factors that may influence the rate of excretion

Answer 19

1. Blood flow- faster means that more drug can be cleared per unit time
2. Kinetics- enzymatic reaction that metabolise the drug- first or zero order reaction for it to be saturated
   - Rate limiting steps may prevent more of that drug to be metabolised

Question 20

When does excretion start occurring?

Answer 20

As soon as it goes into the blood plasma

Question 21

What is elimination kinetics? And explain first order and zero order in terms of this?

Answer 21

Overcoming the rate of absorption:

First order: can be used to show the half life at 50% of a drug being eliminated in the body

Zero order: just dictated by the amount of drug in the blood plasma and whether it’s saturated or not- set limit