Unit 2 - Oral Absorption 1

Question 1

Give examples of formulations that are taken orally

Answer 1

Tablets
Controlled release tablets
Capsules
- soft
- hard
Suspensions
Micro/nanoparticles
Micro/nanoemulsions
Liquids

Question 2

What is the major absorption barrier to oral formulations?

Answer 2

Small intestine

Question 3

What are the small intestine villi covered by?

Answer 3

Intestinal epithelial cells

- enterocytes

Question 4

Which surface are microvilli found on enterocytes?

Answer 4

Apical surface

- the surface facing the intestinal lumen

Question 5

Which parts of the body produces mucus?

Answer 5

Oesophageal/gastric/intestinal mucosa
Nasal/olfactory mucosa
Lung mucosa
Buccal mucosa
Genitourinary tract

Question 6

What is mucus made of?

Answer 6

Water
- up to 95%
Mucin
- no more than 5%
Inorganic salt
- about 1%
Carbohydrates and lipids

Question 7

What is mucin made of?

Answer 7

80% carbohydrate by weight

Question 8

Which cells produce mucus?

Answer 8

Goblet cells within the epithelium

Serous cells of the submucosal tissue

Question 9

How does mucin form a network?

Answer 9

Disulphide bonding

Question 10

How does mucus change with pH?

Answer 10

Neutral pH - viscoelastic solution
Low pH - soft viscoelastic gel
viscosity changes

Question 11

What factors affect the residence time of drug(how long the drug is there) in solution at absorption surface?

Answer 11

Gastric emptying

Intestinal motility

Question 12

What is the major site of absorption within the small intestine?

Answer 12

Jejunum

Ileum

Question 13

What are the advantages of sublingual and rectal delivery of drugs?

Answer 13

Partially avoids 1st pass
1st pass metabolism: the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation. It is the fraction of drug lost during the process of absorption

Question 14

What factors affect what fraction of drug can get into a solution in the lumen of the gastrointestinal tract?

Answer 14

Disintegration
Dissolution
Complexation
Chemical/enzymatic degradation

Question 15

What factors affect what fraction of drug passes through the mucosal barrier into the portal vein?

Answer 15

Membrane permeability

Metabolism

Question 16

What factors affect what fraction of drug passes into the general circulation from the liver?

Answer 16

Metabolism liver enzyme

Biliary excretion

Question 17

How might the liver effect bioavailability ?

Answer 17

This first pass through the liver thus may greatly reduce or increase the bioavailability of the drug.

Question 18

What factors affect bioavailability?

Answer 18

Formulation
Permeability
Solubility
Transit time/available absorption surface
Lability
- chemical
- enzymatic

Question 19

What is rate of bioavailability?

Answer 19

How fast the drug absorbed into the systemic circulation

Question 20

How is the rate of bioavailability measured?

Answer 20

First-order absorption rate

Time to maximum drug concentration

Question 21

What is the extent of bioavailability?

Answer 21

How much of the drug dose is absorbed into the systemic circulation

Question 22

How is the extent of bioavailability assessed? (on a conc vs time curve)

Answer 22

Maximum drug concentration
Area under the curve (AUC) on a concentration vs time curve
- a measure of exposure

AUC is a combined function of dose available to systemic circulation and drug clearance

AUC represents total drug exposure across time

Question 23

What is Lipinski’s Rule of 5?

Answer 23

5 parameters to suggest whether a drug will have the correct physiochemical properties

Poor ‘oral’ absorption predicted for molecules with:
> 5 H-bond donors (sum of OHs & NHs)
> 10 H-bond acceptors (sum of Ns & Os, halogens)
MW > 500
CLogP > 5 (or MLogP > 4.15)

Question 24

What in-vitro permeation (studies across biological membranes for formulations) studies are carried out?

Answer 24

PAMPA
- permeation across artificial membranes
CACO2
- permeation through a cellular barrier

Question 25

What is the Biopharmaceutics Classification System?

Answer 25

Permeability vs solubility chart Class 1 - high solubility, high permeability Class 2 - Low solubility, high permeability Class 3 - high solubility, low permeability Class 4 - Low solubility, low permeability

Question 26

How does the stomach behave in the fasted state?

Answer 26

Phases defined by MMC - migrating myoelectric complex - bursts of smooth muscle activity

Question 27

How often is the MMC repeated in a stomach's fasted state?

Answer 27

Every 1.5 - 2 hours until a meal is ingested

Question 28

What are the four phases in the fasted state of the stomach?

Answer 28

``` Phase I - approximately 45 - 60 mins - no to rare contractions Phase II - approximately 30 - 45 mins - intermittent contractions - increase in strength and frequency Phase III - approximately 5 - 15 mins - highest contraction strength - empties large solid particles from stomach Transition phase - approximately 20 mins ```

Question 29

How are liquids managed in the fasted state of the stomach?

Answer 29

< 150 ml - no change in gastric emptying pattern - most liquid emptied as bolus in phase II/III Large volumes - convert pattern to one of fed state - immediate and continuous emptying of liquid

Question 30

How does the stomach behave in the fed state?

Answer 30

``` No phases with contraction only moderate in strength Contractions - peristaltic and systolic to diminish size of stomach - cause mixing and grinding - gastric emptying of solids is slowed - greater volume of food - solid nature - higher fat content ```

Question 31

How is gastric emptying important in the fasted state?

Answer 31

Drug as particle or in solution? Calorific value of solution? Solution - 5 - 50 mins Particle - 5 - 2 hours

Question 32

How is gastric emptying important in the fed state?

Answer 32

Solid or solution induced fed state? Calorific value? ``` Solution induced > 150ml - 5 mins - even for drug in particle Food induced - drug particle likely to remain distributed with solid food - emptying every 0.5 - 5 hours ```

Question 33

How long does it take material to travel through the small intestine?

Answer 33

3 - 5 hours independent of food

Question 34

How long does it take material to travel through the large intestine?

Answer 34

15 - 60 hours | + average 24 hours

Question 35

How does food change absorption of drug?

Answer 35

Food changes the gastro-intestinal motility to a fed state - slows gastric emptying Stomach contents released into intestine stimulates release of bile salts - help absorption of fats High fat meal - help a very hydrophobic drug to dissolve - more of the hydrophobic drug in solution at absorption site promotes increased extent and rate of absorption

Question 36

When is delayed gastric emptying undesirable?

Answer 36

Rapid onset of action is needed - made worse when absorption occurs in distal part of intestine - takes longer to reach it as further away Stability of drug is compromised at low pH - stays longer in the stomach surrounded by stomach acid Disintegration/dissolution of medicine best at higher neutral/alkaline pH - takes longer to reach the more alkaline small intestine

Question 37

How does food content affect gastric emptying and drugs?

Answer 37

Foods tend to decrease the rate of gastric emptying Food forms complexes with drugs Food may affect absorption - high fat particularly prolongs gastric emptying time

Question 38

When is delayed gastric emptying desirable?

Answer 38

When it is an aid to disintegration/dissolution process

Question 39

Why does phenoxymethylpenicillin (penicillin V/VK) have to be taken on an empty stomach?

Answer 39

Exposure to acid with prolonged gastric residence leads to chemical degradation and reduced biavailability with risk of therapeutic failure

Question 40

Why does saquinavir have to be taken with meals?

Answer 40

* food changes the gastro-intestinal motility to a Fed-state - slows gastric emptying * stomach contents released into intestine stimulates release of bile salts that help absorption of fats * high fat meal can help a very hydrophobic drug to dissolve * more of the hydrophobic drug in solution at absorption site promotes increased extent and rate of absorption. Foods tend to decrease the rate of gastric emptying Bile acids released assist solubilisation and enhance drug dissolution - high fat meals can also enhance extent of absorption - Saquinavir bioavailability doubles with high fat cooked breakfast

Question 41

Why do bisphosphonates have to be taken on an empty stomach?

Answer 41

Calcium and other cations in food can form insoluble chelates

Question 42

Why do fluoroquinolones have to be taken on an empty stomach?

Answer 42

Form slightly soluble complexes with metal ions | - reduced bioavailability

Question 43

Why does ciprofloxacin have to be taken on an empty stomach?

Answer 43

Casein and calcium present in milk decrease the absorption

Question 44

Why does tetracycline have to be taken one hour before, or two hours after meals, and not taken with milk?

Answer 44

Binds calcium and iron forming insoluble chelates - reduces bioavailability Even a little quantity of milk containing extremely small amounts of calcium severely impair the absorption of the drug - tea - coffee