Pharmacokinetics: Metabolism & Elimination

Question 1

Where does metabolism occur?

Answer 1

Tissue level = liver, kidney (filter), lungs

Intracellular level = mitochondria, smooth ER

Question 2

Why does the body metabolise the parent compound in the metabolite?

Answer 2

Trying to convert parent compound into something that’s more amenable to excretion (urine) = more polar = more water-soluble
= reduction in biological activity
However metabolism can sometimes increase biological activity as well

Question 3

Describe the stages of metabolism

Answer 3

Phase I               Phase II
Drug ------> Metabolite ------> Conjugate
Drug = parent compound
Metabolite = derivative
Conjugate = add ons

Question 4

What occurs during Phase I of metabolism?

Answer 4

Preparing drug for conjugation (e.g. opening up functional groups)
3 main reaction occur to change the drug’s structure:
Oxidation
Reduction
Hydrolysis

Question 5

What is the role of Cytochrome P450 in Phase I metabolism?

Answer 5

Isoenzymes, found in smooth ER

Variety within family to metabolise a variety of compounds in order to prepare them for conjugation

Question 6

Explain how cytochrome P450 prepares a compound for conjugation

Answer 6

Drug molecule interacts with cytochrome P450 enzyme
It becomes oxidised (remove electrons)
Compound (metabolite) is now ready for conjugation

Question 7

What occurs during Phase II metabolism?

Answer 7

Reactions which involve the formation of covalent bonds
This results in a water-soluble conjugate = can be excreted in urine more easily
Products of Phase II are often inactive, however in some cases activity is retained
e.g. codeine –> morphine = increased analgesic effects

Question 8

When does first pass metabolism occur?

Answer 8

Metabolism begins before the drug reaches the general circulation

Question 9

Which sites in the body are involved in first pass metabolism?

Answer 9

Liver
Lung
Intestinal lumen
Intestinal wall

Question 10

List 2 factors which influence metabolism

Answer 10

Genetic influences e.g. enzymes, genes

External factors e.g. grapefruit (increases Cp as it inhibits CYP3A4 enzyme)

Question 11

List 3 types of drug which should not be combined with grapefruit juice

Answer 11

Statins
Immunosuppressants
Calcium channel blockers

Question 12

Explain the 4 types of metabolisers

Answer 12

Poor metabolisers = inherited a non-functional gene from each parents = no CYP2D6 activity
Intermediate metabolisers = inherited 1 non-functional gene = some CYP2D6 activity
Ultra rapid metabolisers = higher than normal CYP2D6 activity
Extensive metabolisers = most people have at least 1 functional gene = normal CYP2D6

Question 13

List 3 routes of excretion

Answer 13

In:
Fluids = urine, bile, sweat (important for low MW compounds)
Solids = faeces, hair (important for high MW compounds, some drugs passing straight the body)
Gases = expired air (important for volatile compounds, e.g. ethanol for breathalyser)

Question 14

List the 3 main stages of renal excretion

Answer 14

Glomerular filtration
Tubular secretion
Reabsorption

Question 15

Explain the stage of glomerular filtration during renal excretion

Answer 15

Occurs under hydrostatic pressure
Pores allow passage of small molecules (below 20 kDa)
Filtrate contains about 20% of the plasma volume delivered
Molecules = small, low MW, water soluble, unbound

Question 16

Explain the stage of tubular secretion during renal excretion

Answer 16

Renal tubule has secretory transporters on both basolateral and apical membranes
These can transport basic or acidic compounds
This can result in a rapid decrease of Cp of unbound drug = rapid dissociation of any drugs bound to proteins in the plasma so it can be cleared from the body

Question 17

Explain the stage of reabsorption during renal excretion

Answer 17

Body wants to retain some constituents of the glomerular filtrate
Uptake processes exist for carbohydrates, A.A’s etc
Some drugs hijack these systems as substrates for the uptake processes

Question 18

What is enterohepatic cycling?

Answer 18

The circulation of substances (e.g. bile salts) which are absorbed in the intestine, transported to the liver, secreted into the bile and again enter the intestine

Question 19

How does enterohepatic cycling affect the concentration of a drug?

Answer 19

It regulates the Cp of certain drugs (those that conjugate with glucuronic acid) by stopping the body breaking it down with enzymes when the compound is actually required = maintains Cp
e.g. NSAIDs, morphine, oral contraceptives

Question 20

Explain in detail how drugs become involved in the enterohepatic circulation

Answer 20

Drugs that conjugate the glucuronic acid enter the bile
These conjugates are too polar (ionised) so remain in the gut and are broken down by enzymes
This releases the parent molecule which is reabsorbed and processed by the liver again
It is therefore protected against excretion

Question 21

List 2 factors that influence the rate of excretion

Answer 21

Blood flow - increased blood flow = increased excretion

Kinetics - ability of enzymes to become saturated, rate-limiting step, 1st order or 0 order for metabolism

Question 22

What affect does the order of a reaction have on excretion?

Answer 22

1st order = faster excretion when higher Cp
0 order = same rate of excretion regardless of Cp
This is because of enzyme saturation