Lecture 2 Absorption

Question 1

What are the 3 consecutive processes of GI absorption?

Answer 1

1) Disintegration and dissolution
2) Passive diffusion and mediated-transport
3) First-pass metabolism

Question 2

What are the drug factors affecting GI absorption?

Answer 2

1) Release characteristics of dosage form
2) Solubility of drug
3) Ionisation of drug
4) Partition Coefficient of drug
5) Size

Question 3

What are the physiological factors affecting GI absorption?

Answer 3

1) Gastric Emptying Rate/ Intestinal motility
2) Perfusion of GIT
3) Permeability of gut wall
4) Any form of diseases/ surgeries

Question 4

What are the three ways for drug to cross the GI membrane?

Answer 4

1) Passive Transcellular (Cross membrane by itself)
2) Facilitated Transcellular (With help of ion channels or transporter)
3) Paracellular (Pass through junctions)

Question 5

What is Fick’s first law of diffusion?

Answer 5

dQ/dt = Ka*A(GI)
Net rate of transport (Amt/time) = Absorption rate constant (/time) x Amount of drug in GI lumen (Amt)

Question 6

What is the cut off size for Paracellular transport?

Answer 6

> 350 g/mol

Question 7

What are the downsides for drugs that are too lipophilic?

Answer 7

1) Poor water solubility
2) Greater propensity to bind to membrane transporters

Question 8

Where is the main site of absorption in the body?

Answer 8

Small intestine

Question 9

What are the 4 factors that decide the main site of absorption in the body?

Answer 9

1) Surface area (200m^2)
2) Blood flow (1L/min)
3) Sink Condition
4) More permeable membrane

Question 10

What is the rate-limiting step in drug absorption?

Answer 10

Gastric Emptying Rate

Question 11

What are the 3 factors that affect GI motility?

Answer 11

1) Meals (Generally decrease)
2) Physical state of gastric contents (Liquids empties faster than solids)
3) Drugs (Anticholinergic reduces GER, Cholinergic increases GER)

Question 12

Laying on which side increases GER?

Answer 12

Right side

Question 13

What would be affected by the rate of absorption?

Answer 13

Tmax and Cmax

Question 14

What would be affected by the extent of absorption?

Answer 14

Cmax and AUC

Question 15

What are the different types of transporters and examples?

Answer 15

Uptake (Peptide transporter 1 PepT1, Organic anion-transporting polypeptide 3 OATP3) and Efflux (P-Glycoprotein)

Question 16

What enzymes can be found on the gut membrane that metabolises drugs?

Answer 16

CYP450 (CYP3A4, CYP2D6)

Question 17

What are the three fractions to take note of when calculating F?

Answer 17

1) Fa: Fraction that enters intestinal tissues; escaping loss via feces or metabolism from surface enzymes
2) Fg: Fraction reaching portal vein; metabolism within gut wall
3) Fh: Fraction leaving liver; escaping hepatic extraction

F = Fa x Fg x Fh

Question 18

What happens to Penicillin G when taken orally?

Answer 18

Acidic hydrolysis

Question 19

What happens to Insulin when taken orally?

Answer 19

Enzymatic hydrolysis

Question 20

What happens to fexofenadine when taken orally?

Answer 20

Good substrate of efflux transporter and gets shot out

Question 21

What are the reactions that may reduce absorption?

Answer 21

1) Adsorption (Eg. Charcoal)
2) Conjugation (Eg. Sulfoconjugation, Glucuronidation)
3) Decarboxylation
4) Good substrate efflux transporters
5) Hydrolysis (Acid/ Enzymatic)
6) Oxidation
7) Reduction

The reactions increase water solubility of drug reducing permeation or it sticks to drug and prevents absorption.

Question 22

What is a suitable site of administration for a large (MW 1449 g/mol), water soluble, ionised, polar base drug like Vancomycin?

Answer 22

IM and SC sites due to the presence of porous capillary membranes (large fenestrations)

Question 23

Factors affecting absorption from IM and SC sites?

Answer 23

1) Muscle groups
2) Site (IM vs SC)
3) Blood flow
4) Diseases

Question 24

How do you measure permeability?

Answer 24

[Diffusion Coefficient x Partition Coefficient]/ Thickness

Question 25

How do you measure absorption rate constant?

Answer 25

[Permeability x Surface Area]/ Volume of GI lumen

Question 26

Why is the colon not as effective at absorption?

Answer 26

1) Smaller surface area than small intestine
2) Tighter junction than small intestine
3) More efflux transporters found on apical membrane
4) Bacteria affects drugs

Question 27

Why should you not give drugs with a low F orally?

Answer 27

Drugs with low F are more susceptible to variability where as 0.0001 change to 0.001 is equivalent to a 10 fold increase which may severely affect the AUC and effect of the drug

Question 28

True/False: Inter-individual variability is due to polymorphism of transporters

Answer 28

True

Question 29

Why higher perfusion rate equals to higher Cmax?

Answer 29

Because absorption rate is perfusion rate limited. If perfusion rate increases, rate of absorption increases; Cmax increases and Tmax decreases

Question 30

How is Cmax, Tmax and AUC affected when drug is taken with a meal?

Answer 30

All increases