Gastrointestinal Physiology 3

Question 1

What is the role of the small intestine?

Answer 1

Highly adapted for digestion and absorption

Has to be extremely efficient, if we don’t absorb enough nutrients then we cannot survive

Question 2

How is the small intestine adapted to its function?

Answer 2

Large surface area
Minimal epithelial barrier
Enzymes

Question 3

How does the small intestine achieve such a large surface area?

Answer 3

The surface of the small intestine possess fold like structures called plicae
These are also small finger like projections called villi (roughly 1mm in height)
Each villus is lined with a layer of epithelial cells
On the surface of these epithelial cells are many more tiny finger like projections called microvilli
This large surface area is in contact with the contents of the intestine

Question 4

Calculations estimate the area of the small intestine to be equivalent to the size of a…

Answer 4

Tennis court

Question 5

How does the small intestine achieve a minimal epithelial barrier?

Answer 5

The lining layer of the small intestine is only 1 cell thick
This means the barrier between the internal environment of the body and the contents of the small intestine is only 1 cell thick (can’t get much smaller)

Question 6

What are the vast majority of the cells lining the small intestine?

Answer 6

Enterocytes

Question 7

What is the role of enterocytes?

Answer 7

Absorb nutrients

Question 8

The small intestine also contains a small number of which cell type?

Answer 8

Goblet cells

Question 9

What is the role of goblet cells?

Answer 9

Mucus producing, aids the transit of material through the GIT

Question 10

What can be found in the centre of each villus?

Answer 10

Lymph duct (lacteal) 
When lipids cross the epithelial barrier they drain down into the lymph duct
Also arteries and arterioles, and veins and venules, the small intestine has a very good blood supply

Question 11

The apical membrane faces…

Answer 11

The contents of the small intestine

Question 12

Where can enzymes be found in the small intestine?

Answer 12

Expressed/located in the apical membrane of epithelial cells

Question 13

What is the function of enzymes in the small intestine?

Answer 13

Convert non-absorbable macromolecules to absorbable small molecules
When we take in large proteins, complex carbohydrates etc., we are not able to absorb these, they have to be broken down into much smaller units in order to be absorbed

Question 14

How does carbohydrate digestion occur in the small intestine?

Answer 14

Sucrose, lactose and maltose are all disaccharides and are too large to cross the apical membrane so are broken down by sucrase, lactase and maltase respectively

Question 15

Give the equations for carbohydrate digestion in the small intestine.

Answer 15

Sucrose (sucrase) → Glucose + Fructose
Lactose (lactase) → Glucose + Galactose
Maltose (maltase) → Glucose + Glucose

Question 16

What happens to the carbohydrates once they have been broken down into monosaccharides?

Answer 16

Once broken down, monosaccharides are transported into enterocytes
The transporters involved vary on which monosaccharide it is being absorbed

Question 17

How are glucose and galactose absorbed?

Answer 17

Glucose and galactose enter enterocytes via the SGLT1 transporter
Requires a high concentration of Na+ cells in the lumen in order to work as Na+ binds along with glucose or galactose

Question 18

How is fructose absorbed?

Answer 18

Fructose enters enterocytes via the GLUT5 transporter

Does not require Na+ ions for uptake

Question 19

What happens to these monosaccharides once they have been transported?

Answer 19

Now inside the enterocyte, the monosaccharides diffuse across the basolateral membrane and into the bloodstream (more transporters are involved here to move the molecules out of the enterocyte)

Question 20

How does protein digestion occur in the small intestine?

Answer 20

Need to break large protein molecules down into smaller units (small peptides and amino acids)
Proteases (also present in the stomach) are embedded in the apical membrane
When proteins come into contact with these they are chopped into smaller units

Question 21

What happens to the proteins once they have been broken down into small peptides and amino acids?

Answer 21

Transported across the apical membrane into enterocytes by PEPT1 transporters
This transporter needs H+ in order to work

Question 22

What is a problem associated with hydrophilic drugs?

Answer 22

They dissolve well in solution in the intestine, but are very difficult to get into the body as they don’t have the right chemical and physical characteristics to diffuse into the body and through lipid membranes
This has an impact on bioavailability

Question 23

How can this problem (with hydrophilic drugs) be overcome?

Answer 23

Absorption via uptake transporters is extremely efficient (need to get nutrients, iron etc. into the body in order to stay alive)
This has been exploited by drug designers
They have studied the chemical structures of some natural products, and attempted to synthesise drugs to look like these natural products
These drugs can ‘fool’ the transporter into moving it across the membrane and into the enterocyte

Question 24

Give some examples of drug PEPT1 substrates.

Answer 24

Cephalosporins
Penicillins
Enalapril
α-Methyldopa-phenylalanine 
Val-acyclovir

Question 25

Give some examples of drug organic cationic transporter (OCTN2) substrates.

Answer 25

``` Quinidine Verapamil Imatinib Valproic acid α-Methyldopa-phenylalanine Val-acyclovir ```

Question 26

Give some examples of drug organic anion transporting polypeptide (OATP2B1) substrates.

Answer 26

Pravastatin Rosuvastatin Atorvastatin Fexofenadine

Question 27

Which type of transporter is beneficial to drug delivery?

Answer 27

Uptake transporters (things are taken up from the gut lumen into the body)

Question 28

Which type of transporter can be detrimental to drug absorption?

Answer 28

Drug efflux transporters | Also found in the apical membrane

Question 29

Where can drug efflux transporters be found?

Answer 29

Throughout the body in the intestine, liver and kidney

Question 30

How are drug efflux transporters important in pharmacokinetics (PK)?

Answer 30

Affect absorption in the intestine | Also important once drugs are in circulation as they can pump drugs out in the liver and in the kidney into the urine

Question 31

Where are drug efflux transporters highly expressed and what problem does this pose?

Answer 31

Capillaries in the brain | Major problem in delivery of drugs to the brain

Question 32

How do drug efflux transporters work?

Answer 32

Drugs move into enterocytes Efflux pumps located in the membrane grab the drug and throw it back out into the lumen This is an active process (uses ATP as energy to drive it)

Question 33

What are 2 of the main efflux transporters in the intestine?

Answer 33

P-glycoprotein (P-gp) Breast cancer resistance protein (BCRP) (named this way as expressed in some breast cancer cells and was found in research to reduce the amount of toxic chemotherapeutic drug entering the cancer cell)

Question 34

Which drugs are substrates to the P-gp transporter?

Answer 34

HIV PI e.g. Indinavir Immunosuppressants e.g. CsA, Tacrolimus Antibiotics e.g. Erythromycin Cardiotonics e.g. Digoxin, Quinidine (some of these drugs have a narrow therapeutic window) Verapamil (pumped in by OCTN2, out by p-gp, competing transporters) Quinidine (pumped in by OCTN2) Imatinib (pumped in by OCTN2)

Question 35

In which condition are drug efflux transporters particularly problematic?

Answer 35

Cancer

Question 36

How can we bypass the problem of drug efflux transporters in cancer?

Answer 36

By using an infusion of chemotherapeutic drug

Question 37

What problems does this solution to bypass the transporter cause in itself?

Answer 37

When the needle is removed from the patient, a little bit of the drug 'leaks' out, or if the drug leaks out of a blood vessel (extravasation), can cause necrosis (drug is very toxic, it is diluted once in the blood so isn't as toxic)

Question 38

How would anti-cancer drugs ideally be formulated?

Answer 38

As oral formulations

Question 39

How could the problems associated with taking anti-cancer drugs orally, namely drug efflux transporters, be overcome?

Answer 39

By having the patient take a p-gp modulator (inhibitor) among with the anti-cancer agent Leads to more of the anti-cancer agent being absorbed This however does need to be balanced with toxicity, increased absorption = increased toxicity

Question 40

Give some examples of oral anti-cancer agents.

Answer 40

Etoposide (anti-cancer drug) formulated with valspodar (p-gp modulator) Doxorubicin formulated with valspodar Paclitaxel formulated with VX-710

Question 41

Drug efflux transporters are also relevant for...

Answer 41

Drug-drug interactions in patients | Runs the risk of toxicity

Question 42

Name 3 clinical p-gp drug-drug interactions.

Answer 42

Digoxin and Ritonavir (blocks pump) - increase in digoxin AUC Digoxin and Atorvastatin - increase in digoxin AUC Digoxin and Talinolol - increase in digoxin AUC