L2 - Oral Dosing and Absorption Concepts

Question 1

What are the three consecutive processes that govern drug absorption following oral administration?

Answer 1

1. Disintegration and dissolution - release of active drug ingredients from the dosage form.
2. Passive diffusion and mediated transport - translocation of dissolved drug across the GI mucosal barriers.
3. First-pass metabolism in the GI mucosa and liver.

Question 2

What are the factors determining the release and absorption kinetics of a drug following oral administration of solid dosage form?

Answer 2

1. Release characteristics of dosage form
   - disintegration/deaggregation
   - dissolution of drug from granules
2. Physicochemical properties of drug
   - ionisation (acid/base)
   - partition coefficient (octanol/water)
   - solubility in water
3. Physiology of Gastrointestinal Tract
   - colonic retention
   - gastric emptying
   - intestinal motility
   - perfusion of the gastrointestinal tract
   - permeability of gut wall
4. GI tract abnormalities
   - Crohn’s disease
   - Gastric resection (e.g. in obesity)
   - Diarrhea

Question 3

What happens when dissolution&raquo_space; absorption?

Answer 3

permeability rate-limits absorption
e.g. sucralfate (Rx gastric and intestinal ulcers)
less common

Question 4

What happens when dissolution &laquo_space;absorption?

Answer 4

dissolution rate-limits absorption.
changes in dissolution profoundly affect rate and sometimes extent of absorption.
more common

Question 5

What is Fick’s first law of diffusion and the formula for it?

Answer 5

Describes passive diffusion from a site of high concentration to a site of low concentration.
dQ/dt = P.A.(C(GI) - C(P))

Question 6

What are some physiochemical factors that affect the permeability of the drug molecule?

Answer 6

• size of the molecules (the larger the MW, the more difficult it is to pass through the membranes via paracellular transport).
  » Once a molecule exceeds MW350, it fails to cross the GI membrane via paracellular transport.
• lipophilicity of the drug molecules. The more lipophilic the drug molecules, the greater its permeability.

Question 7

Which drug molecules fail to cross the GI membrane via paracellular transport and why?

Answer 7

oxytocin and calcitonin, MW exceeds 350 g/mol

Question 8

What are some limitations of drug molecules as they become more lipophilic?

Answer 8

• they have poorer aqueous solubility

- they have greater propensity to bind to membrane transporters.

Question 9

Acidic drugs are unionised to a greater degree in the low pH environment of the stomach compared to the relatively higher pH environment of the small intestines. Hence there is a greater extent of absorption of acidic drugs in the stomach when they are dosed orally.

Answer 9

Disagree. Ceteris paribus, according to pH partition hypothesis, since a larger proportion of unionised acidic drugs exist in the stomach, the drug should be better absorbed in the stomach.

However, drug is better absorbed in small intestine because there are other extrinsic factors to consider-
it has a larger surface area of 200 square meters, higher blood flow of 1L/min, meets the sink condition and the intestinal epithelial cells have a more permeable membrane.

Question 10

What can you say about the relationship of gastric emptying and speed of drug absorption?

Answer 10

The rate of gastric emptying becomes controlling step in the speed of drug absorption, as a result of absorption of all drugs being faster in the intestine than it is in the stomach.

Question 11

How does GI motility affect drug absorption?

Answer 11

1. Gastric emptying - can control the rate at which the drug is presented to the major site of absorption, that is, the upper small intestine.
2. Intestinal motility - determines the residence time of the dosage form in the small intestine, hence, changes in motility could alter drug bioavailability depending on whether dissolution or permeability is the rate-limiting step.

Question 12

What happens to intestinal motility when dissolution is rate-limiting?

Answer 12

it will slow down, and allow for more complete dissolution and improved bioavailability (extent). Conversely, acceleration in motility can further limit dissolution and bioavailability.

Question 13

What happens to intestinal motility when permeability is rate-limiting?

Answer 13

Slowed motility allows for more time for absorption, thereby compensating for poor permeability.

Question 14

What are some factors that affect GI motility?

Answer 14

1. Meal –> a heavier stomach results in a reduction in gastric emptying rate (decrease in GER)
2. Physical state of gastric content –> solutions or suspensions of particles empty more rapidly than chunks of materials which need to be broken down before emptying.
3. Concomitant administration of drugs:
   - anticholinergic, narcotic analgesics –> decreased gastric emptying rate.
   - metoclopramide –> increased gastric emptying rate.

Pregnancy also affects.

Question 15

What are some takeaways from the gastric emptying and intestinal transit graph?

Answer 15

1. Small, non-disintegrating tablets tend to have better absorption, therefore lower transit time in the small intestine than large, non-disintegrating ones.
2. The more food you consume, the longer the transit time in the stomach.
3. Food does not affect the transit time in the small intestine, the small intestine will digest most of the food in 3-4 hours tops.

Question 16

What are some takeaways from the case study of the GI absorption of acetaminophen with the co-administration of remifentanil, and the body position that it is administered in?

Answer 16

• GI absorption of acetaminophen is affected by co-administration of remifentanil and body position?
• Main site of absorption is small intestine. Body position affects gastric emptying rate.
• When rate of drug absorption is faster, Tmax is shorter and Cmax is higher.
• Require AUC to conclude the extent of absorption in the small intestine.

Question 17

What are some properties that vary in the GIT?

Answer 17

1. surface area per unit length
2. electrical resistance
3. metabolic enzymes and transporters
4. anaerobic microbes
5. pH
6. mean transit time

Question 18

How does surface area per unit length vary across the GIT?

Answer 18

decreases from duodenum to rectum

Question 19

How does electrical resistance (tightness of junction) vary across the GIT?

Answer 19

higher in colon than small intestine

Question 20

How do metabolic enzymes and transporters vary along the GIT?

Answer 20

They are distributed variably throughout the GIT.
Transporter expression differs between apical (facing lumen) and basolateral (facing vilous blood), and can change along the length of the membrane.
P-glycoprotein efflux pump’s activity increases along the GIT.

Question 21

How do anaerobic microbes distribute themselves in GIT?

Answer 21

they are abundant in colon.

Question 22

How does pH vary in the GIT?

Answer 22

pH 6.6 (proximal small intestine) –> pH 7.5 (terminal ileum) –> pH 6.4 (caecum) –> pH 7.0 (descending colon)

Question 23

How does mean transit time differ along the GIT?

Answer 23

3-4hr (small intestine), 10-36hr (large bowel)

Question 24

What is the takeaway of the GI absorption of polar drugs with ranitidine as an example?

Answer 24

1. A drug may be polar if it has low MW but still poor absorption.
2. The primary site of absorption of the drug is determined based on where there is the largest drop in drug concentration, and not based on the length of time that it spends in the organ.

Question 25

How is CYP3A4 able to achieve significant intestinal first-pass effect?

Answer 25

As a result of residing at the apical side of the intestinal epithelium, the enzyme allows for coupling of efflux transport and metabolism that results in significant intestinal first-pass.

Question 26

What type of transporter is P-glycoprotein?

Answer 26

efflux

Question 27

How do you calculate the total bioavailability, F of the drug?

Answer 27

F = Ff . Fg. Fh

Question 28

How do you calculate the fraction of drug that is lost at each step?

Answer 28

1-Ff, 1-Fg or 1-Fh

Question 29

What are some examples of intestinal wall interactions?

Answer 29

Coupling effects luminal efflux transport and metabolism within intestinal cells.

Question 30

(T/F): drugs administered according to the i.m. route experience low impedance by porous capillary membrane, only on the condition that they are uncharged, unionised, and have a smaller molecular size.

Answer 30

False. Drugs administered by the im route have low impedance by porous capillary membrane regardless of the three attributes.

e.g. vancomycin (water soluble, ionised, polar base with large MW)

Question 31

Under what conditions does blood flow and rate of absorption get reduced?

Answer 31

vasoconstriction and shock

Question 32

Under what conditions does blood flow and rate of absorption increase?

Answer 32

heat, fever and exercise

Question 33

(T/F): absorption of drug in solution from muscle and subcutaneous tissue is perfusion rate-limited.

Answer 33

true