F4+F8 Gastrointestinal absorption Flashcards
1
Q
is the GIT a uniform structure? explain
A
- no
- it is composed of several regions
- these regions differ in anatomy, amount of fluids, biochemical environment, pH, microbial flora, expression of transporters and absorption characteristics
2
Q
what is the main function of the stomach?
A
- processing food
- primarily a processing organ, not an absorptive one
3
Q
state 2 substances that have substantial absorption in the stomach
A
ethanol
aspirin
4
Q
why is there little absorption in the stomach for most drugs compared to the small intestine? take into account total absorptive area, perfusion and low permeability of membranes
A
stomach
- total absorptive area: 1 metre squared (small area for absorption)
- perfusion: 150ml/min (relatively low compared to small intestine)
- low permeability of membranes
small intestine
- total absorptive area: 200 metres squared (larger area for absorption)
- perfusion: 1 L/min (high perfusion by blood compared to the stomach)
- high permeability of membranes
5
Q
explain how the environment of the stomach plays a part in the importance of the stomach in absorption of drugs
A
- the human stomach secretes 1-1.5L of gastric juice per day (highly acidic and rich in enzymes)
- the pH ranges from around 1.5-2 (fasting) to 3-6 (fed)
- this environment affects solubility, ionisation and stability of drugs
6
Q
explain how the motility of the stomach plays a part in the importance of the stomach in absorption of drugs
A
- gastric emptying time is highly variable (transit time 0-2h)
- presence of food, size of the meal, as well as food or formulation components will greatly affect gastric emptying time, and therefore the rate of absorption of drugs
7
Q
describe the small intestine as the main absorption site of the GIT
A
- primary function is digestion and absorption
- large surface area available for absorption
- highly perfused
- transit time is 3-4 hours (less variability than stomach)
8
Q
what is the small intestine highly perfused by?
A
blood capillary
lymphatic lacteals
9
Q
state 3 structures that increase the surface area of the small intestine
A
- folds of Kerckring
- villi
- microvilli
10
Q
by what fold do folds of Kerckring, villi and microvilli increase the surface area of the small intestine by?
A
- folds of Kerckring: 3 fold
- villi: 30 fold
- microvilli: 600 fold
11
Q
what does high perfusion of the small intestine allow for?
A
maintenance of concentration gradients so diffusion can continue to occur constantly
12
Q
describe the process of mixing in various areas of the small intestine
A
- unstirred layer close to intestinal epithelium is the area of the lumen of the intestine that isn’t as well mixed by peristalsis as the contents at the centre of the lumen
- process of mixing isn’t as efficient as you get closer to the intestinal epithelium
13
Q
in the unstirred layer of the small intestine contents, how do drugs cross the intestinal membrane?
A
- drug must be in solution to be absorbed
- dissolved particles move through unstirred layer and mucus by diffusion to the epithelium
14
Q
state the 3 barriers that drug molecules should overcome in order to arrive to the membrane of the enterocyte
A
- solubility in the aqueous environment of GIT lumen
- presence of unstirred water layer and mucus
- chemical and enzymatic stability in the GIT lumen
15
Q
what is an enterocyte?
A
intestinal absorptive cells
16
Q
describe the barrier that drugs must overcome to reach enterocytes: solubility in the aqueous environment of GIT lumen
A
- in the vast majority of cases a drug must solubilise in the GIT lumen before it can be absorbed
- the solubility will depend on hydrophobicity and pKa of the drug, pH and environment in the GIT
17
Q
describe the barrier that drugs must overcome to reach enterocytes: presence of unstirred water layer and mucus
A
- because this layer is static, drug movement is by diffusion which is relatively slow (large and hydrophobic drugs will diffuse slower)
18
Q
describe the molecules that arrive to the enterocyte membrane easily
A
small
stable
hydrophilic
ionised
19
Q
describe the molecules that arrive to the enterocyte membrane with problems (slowly and incompletely)
A
large
unstable
hydrophobic
unionised
20
Q
what is the most important factor of molecules for them to reach the membrane of the intestinal membrane?
A
their solubility in the aqueous environment
21
Q
describe the cell junctions in the intestine and the proteins in their membranes
A
- the junctions between epithelial cells of the intestine are of a ‘tight junctions’ type
- specific proteins in 2 adjacent membranes make direct contact across the intercellular space
22
Q
describe absorption by intercellular route and explain why it happens
A
- because of the tight junctions the membranes are within 2 Angstroms of each other (0.2 nm)
- although some small hydrophilic molecules can be absorbed by intercellular route, this transport is less common and less important than transcellular transport of drugs
23
Q
what needs to happen for absorption from the intestinal lumen into the systemic circulation by the transcellular route?
A
- the drug needs to pass across multiple barriers
- eg. in most cases it should be able to pass across cell membranes
24
Q
what makes a drug a drug?
A
ability to penetrate membranes is what makes a drug a drug
25
most drugs penetrate membranes by what method?
passive diffusion
26
what equation is the rate of passive diffusion described by? what does each symbol of the equation represent?
Fick's law
- R = diffusion rate (mol/s)
- A = area of the membrane over which the diffusion is occurring
- ΔC = concentration difference between two sides of membrane
- ΔX = membrane thickness
- D = a constant for a specific molecule in a specific conditions
27
why does D has a minus sign in Fick's law?
- this has a minus sign because diffusion happens from high concentration to low concentration
- this is the aspect of the equation that we have control over because we can choose substances with preferable diffusion coefficients
28
which element of the Fick's law equation is drug-dependent?
- only D
- will determine which drug would penetrate the membrane by passive diffusion (and would be absorbed), to what extent and how quickly
29
what are the most important physicochemical properties that determine the diffusion coefficient for a specific molecule?
partition coefficient (P)
molecular weight (MW)
30
describe the partition coefficient (P)
- indication of lipophilicity of a drug
- describes how the drug distributes itself between a pair of solvents when it is in unionised form (eg. octanol and water)
- pH is adjusted with a buffer so that the drug is unionised
- aqueous phase and an oily solvent such as octanol
31
where do hydrophobic and hydrophilic drugs mainly dissolve? describe their partition coefficients
hydrophobic
- mainly dissolve in oil
- high partition coefficient
hydrophilic
- mainly dissolve in water
- low partition coefficient
32
explain the solubility that drug molecules must have in order to be absorbed
- should have some solubility in water
- should also have some solubility in oily membrane
- requires an average P value, not very high or very low
33
explain why drugs that have a very low partition coefficient are poorly absorbed
they can't dissolve in the oily cell membrane
34
explain why drugs that have a very high partition coefficient are poorly absorbed
they can't dissolve in the intestinal lumen and won't reach the membrane
35
explain the effect of partition coefficient and molecular weight on relative absorption rate
- middle values of logP are beneficial as shown by bell-shaped curve
- high and low values of logP do not mean the drug won't be absorbed, it just means the drug will be absorbed more slowly
36
what does RTC stand for?
radio telemetry capsule
37
describe the graph showing pH in the human GIT vs time after ingestion of RTC
38
why is the pH more acidic in the colon?
due to the action of bacteria
39
explain how an acidic drug would best penetrate a membrane and its solubility based on the pH-partition hypothesis
- from an acidic environment (eg. stomach)
- but solubility would be higher in basic environment (small intestine)
40
explain how a basic drug would best penetrate a membrane and its solubility based on the pH-partition hypothesis
- from more basic environment (eg. small intestine)
- but solubility would be higher in acidic environment (stomach)
41
what is meant by a saturable epithelial transporter cell?
there are a limited number of transporters per cell
42
what is meant by absorption windows in the gut?
specific ligand taken up in specific parts of gut
43
describe the difference between symport and antiport co-transport
symport
- two molecules transported in the same direction (one often being a drug in pharmacology)
antiport
- two molecules being transported in opposite directions (one often being a drug)
44
are vitamins hydrophilic or hydrophobic?
hydrophilic
45
describe and explain the absorption of vitamins
- vitamins are hydrophilic so don't penetrate membranes very well
- we need them so we require transporters to absorb them
- also need transporters to push them on further to their site
46
describe P-glycoprotein
- efflux transporter
- an ATP-dependent transporter that is capable of transportation of an extremely wide variety of drugs OUT of the cell
- one of the most important barriers in intestinal absorption of drugs that are substrates to p-glycoprotein
47
describe the properties of MOST p-glycoprotein substrates
lipophilic or amphiphilic
48
where is p-glycoprotein expressed?
- intestinal epithelium
and also:
- liver
- brain (BBB)
- adrenal gland
- kidney
49
state a type of cell that p-glycoprotein is highly expressed by and what it is responsible for in these cells
- highly expressed by some cancer cells
- responsible for 'multi-drug resistance' of cancer cells
50
what does p-clycoprotein action appear to work in concert with?
CYP450 3A4
51
state properties of molecules that WILL penetrate the enterocyte barrier easily
- small
- hydrophobic
- unionised
- not a substrate to p-glycoprotein
- not a substrate to metabolising enzymes in the intestinal wall
- substrate to influx transporter
52
state properties of molecules that WON'T penetrate the enterocyte barrier easily
- large
- hydrophilic
- ionised
- substrate to p-glycoprotein
- substrate to metabolising enzymes in the intestinal wall
- not a substrate to influx transporter
53
membrane transport by diffusion or by transporters is only feasible for what kinds of molecules? which molecules will not be absorbed these ways?
- only feasible for small molecules
- macromolecules and particles will not be absorbed these ways
54
what process are macromolecules and particles internalised by?
endocytosis
55
what is the difference between pinocytosis and phagocytosis?
pinocytosis
- receptor-mediated or not
- for macromolecules dissolved in fluid
phagocytosis
- for particles up to about 1-2 micrometres
- engulfing or large particles or whole cells
56
what do M-cells do in Peyer's patches?
sample the particles from GIT for antigens and present them to underlying T and B lymphocytes
57
what happens to the particles that are sampled by the M cells of Peyer's patches after they have been sampled?
the particles are then transported to the systemic circulation through the lymphatic system
58
how much material can be transported by the Peyer's patches?
- VERY low amount
- much less than 1% of a dose
- has not been developed to absorb large quantities, just a small mass of particles
59
what principle can the Peyer's patches pathway of absorption by important in?
oral vaccination
60
what are Peyer's patches?
small, specialised aggregates of lymphoid follicles in the wall of the small intestine
61
along the colon, where is there a pH drop?
from the terminal ileum to the ascending colon
62
after the pH drop in the colon from the terminal ileum to the ascending colon, what happens to the pH in the colon?
pH is going up again gradually form the ascending to transverse and descending colon
63
describe colonic bacteria and what they can do
- predominantly anaerobic
- secrete enzymes that are capable of metabolising endogenous and exogenous substances that dodge digestion earlier on in the GIT (carbohydrates, proteins)
64
what can the process of colonic bacteria digestion be used to treat?
- diseases such as ulcerative colitis
- bacteria can also break down prodrugs
65
what is the primary function of the colon?
- absorbing water and electrolytes
66
describe the amount of fluids in the colon (be specific)
- amount of fluids is relatively low
- especially in distal colon
67
describe the structure of the colon
- colon is wider and shorter than small intestine
- microvilli present, but no villi
- has irregular folds which, along with microvilli, increase SA 10-15 times relative to a cylinder
68
what are the irregular folds of the colon called?
plicae semilunares
69
list the stomach, small intestine and colon in order from smallest SA to largest
stomach
colon
small intestine
70
compare the spectrum of metabolising enzymes in the small intestine and colon and explain the total metabolic activity
- spectrum of metabolising enzymes (Phase I and II) are similar in small intestine and colon
- total metabolic activity is higher in small intestine due to larger SA
71
where are drugs absorbed from the colon and upper rectum absorbed into? what does this mean for them?
- portal vein
- therefore subjected for hepatic first-pass metabolism
72
explain why drugs absorbed from the lower rectum and anal canal are not subjected to hepatic first-pass metabolism. give an example of a route of administration that avoids first-pass metabolism
- absorption from these areas does not get them into the portal vein
- eg. drugs from suppositories
73
why is carrier-mediated absorption practically absent in the colon?
- there are no documented active influx transporters unlike in the small intestine
- therefore, absorption happens mostly by passive diffusion
74
compare the expression of efflux transporters in the colon and small intestine, giving an example. explain the effect this difference has
- higher expression of efflux transporters in the colon
- eg. P-glycoprotein
- makes it more difficult for drugs that target P-glycoprotein
75
which 2 features of the colon result in significant absorption of some drugs from the colon?
long residency time
low enzymatic activity
76
on a plasma concentration-time profile after oral administration, describe when absorption and elimination rates change and how this affects the shape of the graph
77
describe the axes on a semi-log graph
y axis is logged
x axis is normal
78
state the 4 steps for working out half-life from a graph
1. choose a concentration, find it on the graph and note down the time point for that concentration
2. halve your first concentration to give you the second concentration needed
3. find the second concentration on the graph and note down the time point
4. the half-life is the difference in time between the two time measurements
79
what equation links k(el) and half-life?
80
in most cases, what does the oral absorption of drugs approximate as?
first order kinetics
81
what is meant by first order kinetics?
the rate of absorption is proportional to the amount remaining to be absorbed
82
sometimes a drug is absorbed at essentially a constant rate. what does this mean in terms of kinetics?
- in this case, the rate of absorption is not dependent on the amount remaining to be absorbed
- zero order, not first order kinetics
83
in first-order kinetics, why does the rate of emptying (of the intestinal lumen) decrease with time as well as the amount of drug in the intestinal lumen?
- rate of emptying will decrease because it depends on the amount of drug remaining in the intestinal lumen
84
describe the shape of the curve 'rate of emptying vs time' in first order kinetics
- rate of emptying declines exponentially with time
- rate of emptying is proportional to the amount of the drug remaining in the lumen and the efficiency of the absorption
- the rate of emptying relative to the drug remaining will be constant
85
when calculating half-lives, what is the difference between Kel and Ka?
- Kel is the elimination rate constant
- Ka is the absorption rate constant
86
in this graph, describe what is meant by the residual plots
- residual plots are the differences between the red and black plots at each time
- these differences values are shown by the green plots
87
state the 4 steps as to how residual plots are calculated and plotted
1. extrapolate the linear part of the concentration-time curve back to t=0 (red line)
2. for each time point, read off concentration from extrapolated line to give the values of C*
3. for each time point, subtract C from C* (black value from red value)
4. plot these values and draw line of best fit to give green line
88
why is it useful to calculate AUC, even if you already know Cmax, Tmax, elimination half-life, elimination rate constant, absorption half-life and absorption rate constant?
because AUC represents exposure to the drug and is used later on to calculate bioavailability
89
state the 4 steps for approximating AUC on a plasma concentration-time graph
1. divide the conc-time graph into trapezoids
2. find the area of all the trapezoids to the last measured point
3. find the area of the trapezoid beyond the last measured point (trapezoid to infinity)
4. add all the areas of the trapezoids together
90
what equation is used to find the area of the last trapezoid to infinity in a AUC calculation?
91
for a drug administered intravenously, what is the equation for rate of elimination?
CL x C
92
for a drug administered intravenously, what is the equation for total amount eliminated?
CL x AUC
93
for a drug administered orally, what equation is true? what does F mean in this equation?
state an equation that is equivalent and can be used to help remember the first one
F x dose = CL x AUC
total amont absorbed = total amont eliminated
F: absolute bioavailability
94
we can't calculate CL and Vd from extravascular administration unless we know what?
- absolute bioavailability
- (can't calculate form plasma cone-time profiles alone)
95
what equation links Vd, k and CL?
96
what equation links Cl, F, AUC and dose?
CL x AUC = F x dose
97
in most cases, it's not practical to calculate CL and Vd from extravascular administration because knowledge of F is needed. explain.
- in order to know absolute bioavailability (F) we need to administer the drug IV
- if we administer the drug IV, we can calculate CL and Vd because we know bioavailability is 100%
- this is not practical
98
definition of absolute bioavailability
fraction of administered dose reaching the systemic circulation in unchanged form
99
what are the 2 major aspects of absolute bioavailability
- rate and extent of absorption across the GI wall
- extent of drug metabolism or breakdown before it reaches the systemic circulation
100
state 4 reasons for reduced oral bioavailability
- loss in the faeces (not absorbed or effluxes by P-glycoprotein)
- decomposition in the lumen
- destruction within the wall of the GIT (intestinal first-pass metabolism)
- destruction within the liver (hepatic first-pass metabolism)
101
state the equation linking F, Ff, Fg and Fh and state what is meant by all 4 parameters
F = Ff x Fg x Fh
F: total bioavailability
Ff: fraction entering intestinal wall tissue
Fg: fraction that survives the destruction in the intestinal wall
Fh: fraction that survives the destruction in the liver
102
why is the equation 'F = Ff x Fg x Fh' often not practical?
we don't have these parameters / values all the time
103
it is impossible to calculate F from plasma concentrations after oral administration alone but supplemental data form IV administration allows for F calculation. state the equation that can be used
104
in this equation, state an important assumption that is made
clearance remains constant after IV or oral administration
105
what route(s) pf administration can this equation be used to calculate bioavailability for?
any extravascular administrations
eg.
oral
subcutaneous
intramuscular etc.
106
specifically described what AUCs are used in this equation
AUCs to infinity
107
describe Lipinski's 'Rule of 5"
- an empirical rule to evaluate drug likeness or determine if a chemical compound has properties that would make it a likely orally active drug in humans
- assesses how likely a drug is to be orally bioavailable
108
state the 4 criteria of Lipinski's Rule of 5
an orally active drug should have no more than one violation of the following criteria:
1. no more than 5 HBDs
2. no more than 10 HBAs
3. a molecular mass less than 500 Daltons
4. a logP not greater than 5
109
in Lipinski's Rule of 5, what is an HBD?
nitrogen or oxygen atom with one or more hydrogen atoms
110
in Lipinski's Rule of 5, what is an HBA?
nitrogen or oxygen atom with a free lone pair of electrons
111
what are Non-Lipinski molecules?
orally active drug molecules that are exceptions to the Lipinski Rule of 5
112
what is the BCS?
- Biopharmaceutics Classification System
- 4 classes (I, II, III, IV)
- classes describe drugs' permeability and solubility
113
describe class I drugs in the BCS
- high solubility
- high permeability
- very good drugs that don't require us to do much for them to be bioavailable
114
describe the permeability and solubility of class II drugs in the BCS
low solubility
high permeability
115
describe the permeability and solubility of class III drugs in the BCS
high solubility
low permeability
116
describe the permeability and solubility of class IV drugs in the BCS
low solubility
low permeability
117
describe the BCS high solubility criteria
a drug substance is considered 'highly soluble' when the highest dose strength is soluble in 250ml or less of aqueous media over a pH of 1-7.5 at 37 degrees C
118
describe the BCS high permeability criteria
a drug substance is considered to be 'highly permeable' when the extent of absorption in humans is determined to be ≥ to 90% of an administered dose based on mass balance determination
