Pr3106 Lecture 2: Oral Dosing & Absorption Concepts

Front 1

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

Back 1

1. Release of active drug ingredients from the dosage form: disintegration and dissolution
2. Translocation of dissolved drug across the GI mucosal barriers: passive diffusion and mediated-transport
3. First-pass metabolism in the GI mucosa and liver

Front 2

What are the various rate limiting steps of GI absorption?

Back 2

1. Permeability rate-limited absorption occurs when dissolution happens more rapidly than absorption
2. Dissolution rate-limited absorption occurs when absorption happens more rapidly than dissolution

Front 3

What are the physicochemical factors of the drug that affect GI absorption?

Back 3

1. Size of the drug (MW < 350 cross very well)
2. Lipophilicity - ↑ lipophilic, ↑ permeable BUT affects aqueous solubility also
3. Degree of ionization - does not really affect, because under sink conditions, equilibrium will shift towards unionized form

Front 4

What is the most important factor determining rate and extent of GI absorption?

Back 4

RATE OF GASTRIC EMPTYING

This is because the absorption of ALL drugs is faster in the intestines than in the stomach. Hence, the rate of gastric emptying controls the rate at which the drug is presented to the major site of absorption.

Front 5

How does GI motility affect drug absorption?

Back 5

(Refer to gastric emptying also.)

Intestinal motility determines the residence time of the dosage form in the small intestine.

• In dissolution rate-limited abs, slow down in motility allows for more complete dissolution and improved %F (extent).
• In permeability rate-limited abs, slow down in motility allows for more time for absorption, hence improved %F (extent).

Front 6

What are some factors that affect GI motility?

Back 6

1. Meals reduce the gastric emptying rate

2. Physical state of gastric content: solutions or suspensions empty more rapidly

3. Drugs: anticholinergic and narcotic analgesics will decrease GER; metoclopramide will increase GER

Front 7

How do these properties change in the GIT?

• Surface area per unit length
• Electrical resistance
• Metabolic enzymes and transporters

Back 7

Surface area per unit length decreases from duodenum to rectum

Electrical resistance is higher in the colon than in the small intenstine

Metabolic enzymes/transporters are distributed variably across the GIT, but there are patterns, e.g. P-gp efflux pump activity increases across the GIT

Front 8

How do these properties change in the GIT?

• Anaerobic microbes
• pH
• Mean transit time
  

Back 8

Anerobic microbes are abundant in the colon

In the proximal small intestine, pH 6.6 → Terminal ileum pH 7.5 → Caecum pH 6.4 → Descending colon pH 7.0

Mean transit time in small intestine 3-4 h → in large bowels 10-36 h

Front 9

What are the components of oral systemic bioavailability? (F = ???)

Back 9

F = FF.FG.FH

FF = fraction that enters intestinal tissues, neither lost in feces nor decomposed in lumen

FG = fraction that reaches portal vein, escaping destruction within walls of GIT

FH = fraction that reaches liver, escaping hepatic metabolism

Front 10

What are the various competing intestinal reactions that may lower the fraction that enters intestinal tissues?

Back 10

• Adsorption
• Conjugation
• Efflux transport
• Hydrolysis
• Microflora-mediated reactions

Front 11

What are some examples of intestinal wall reactions that may lower the fraction reaching the portal vein?

Back 11

Coupling effects of luminal efflux transport and metabolism within the intestinal cells - i.e. drug is taken in, metabolised, the effluxed out

Front 12

What are the features of absorption from IM/SC sites?

Back 12

There is low impedance by capillary membranes in muscle and sc tissues. Hence, charge, degree of ionization and molecular weight (up to 5000) will not affect absorption. Absorption is primarily perfusion rate-limited.

Front 13

What are some ways in which rate of absorption from IM/SC sites are reduced?

Back 13

Decreased blood flow due to

• Vasoconstriction of sites (vasoconstrictor)
  
• Shock

Front 14

What are some ways in which rate of absorption from IM/SC sites are increased?

Back 14

Increased blood flow due to

• Heat / fever
• Exercise