F4. Gastrointestinal absorption Flashcards
Function of the stomach?
-The main function of stomach is processing of food, not absorbing
WHY THERE IS LITTLE ABSORPTION IN STOMACH FOR MOST DRUGS?
-Stomach: total absorptive area 1 m2, perfusion 150ml/min, low permeability of membranes
-Small intestine: total absorptive area 200 m2, perfusion 1L/min, high permeability of membranes
Describe the environment of the stomach
The human stomach secretes 1-1.5L of gastric juice per day – highly acidic and reach in enzymes. The pH ranges from ~ 1.5-2(fasting) to 3-6 (fed). This environment affects solubility, ionisation and stability of drugs
Describe the motility of the stomach
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
Describe the small intestine
-Primary function is DIGESTION and ABSORPTION
-Large surface area available for absorption
-Highly perfused: blood capillary and lymphatic lacteals
-Transit time is 3-4 hours (less variability than stomach)
overview of intestinal drug absorption?
ONE NOTE
In order to arrive to the membrane of the enterocyte the drug molecule should overcome what following barriers?
-Solubility in the aqueous environment of GIT lumen
-Presence of unstirred water layer
and mucus
-Chemical and enzymatic stability
in the GIT lumen
ONE NOTE
Describe solubility in the aqueous environment of
GIT lumen:
-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
Describe the presence of unstirred water layer and mucus:
Because this layer is static, drug movement is by diffusion which is relatively slow (large and hydrophobic drugs will diffuse slower).
Properties of drug molecules – arrival to the membrane of the enterocyte?
Small
Stable
Hydrophilic
Ionised
These molecules will
arrive membrane of intestinal
epithelium easily
ONE NOTE
What is the most important factor in order to reach the membrane of the intestinal epithelium
solubility in the aqueous environment
Describe the epithelium in the small intestine
In the small intestine epithelium has microvilli on the surface to increase area for absorption
(approximately 1000 hair-like structures per cell projecting into the lumen)
Describe the stomach epithelium
In the stomach epithelium does not have microvilli (lower absorptive area)
Describe the junctions between epithelial cells
-The junctions between epithelial cells of the intestine are of a “tight junctions” type
-In these junctions specific proteins in two adjacent membranes make direct contact across the intercellular space
ONE NOTE
Describe absorption by intercellular route
-Because of the tight junctions the membranes are within 2Å (0.2 nm) of each other
-Although some small hydrophilic (highly water soluble) molecules can be absorbed by intercellular route, this transport is less common and
less important than transcellular transport of drugs
Describe transport across cell membranes (transcellular transport)
-In order to be absorbed from the intestinal lumen into the systemic circulation the drug should pass across multiple barriers – e.g., in most cases it should be able to pass across cell membranes
-There are a number of possible mechanisms for transport across membranes, such as simple diffusion or more selective processes
ONE NOTE
What is the main mechanism of absorption?
-Transport Across Cell Membranes by passive Diffusion is the main Mechanism Of Absorption
-Passive diffusion is described by Fick’s law
ONE NOTE
What does Fick’s law tell us about transport across cell membranes?
-From the Fick’s low it is clear that only diffusion coefficient (D) is drug-dependant and will determine which drug would penetrate the membrane by passive diffusion (and would be absorbed), to what extent, and how quickly
-Most important physicochemical properties that determine the diffusion coefficient for a specific molecule are partition coefficient (P) and molecular weight (MW)
Describe the partition coefficient P
P – describes how the drug distributes itself between a pair of solvents when it is in un-ionised form (aqueous phase and an oily solvent such as octanol)
Describe how the hydrophilicity of drugs link to partition coefficient
-Hydrophobic drugs dissolve mainly in the oil and have high partition coefficient
-Hydrophilic drugs dissolve mainly in in the water and have low partition coefficient
Describe how the absorption of drugs link to partition coefficient
-To be absorbed a drug should have some solubility in water and some solubility in oily membrane
-Drugs that have a very low partition coefficient are poorly absorbed because they cannot dissolve in the oily cell membrane
-Conversely, drugs with very high partition coefficient will not be absorbed since they cannot dissolve in the intestinal lumen and will not reach the membrane
Effect of Partition Coefficient and Molecular Weight?
The smaller the molecule, the faster the absorption
ONE NOTE
The pH-partition hypothesis: weak acid versus weak base?
-Based on pH-partition hypothesis, an acidic drug would penetrate the membrane better from acidic environment (stomach), but solubility would be higher in basic environment (small intestine)
-Based on pH-partition hypothesis, a basic drug would penetrate the membrane better from more basic environment (small intestine), but solubility would be higher in acidic environment (stomach)
-Permeability/solubility interplay is a very important concept in biopharmaceutics
The pH-partition hypothesis - issues?
-In fact, absorption of most acidic drugs is better from small intestine (pH 6.6-7.5) than from stomach…Why???
-In addition to luminal pH, factors such as surface area, permeability and blood flow are important for absorption
-Small intestine: total absorptive area 200 m2, perfusion 1L/min, high permeability of membranes
-Stomach: total absorptive area 1 m2. perfusion 150ml/min, low permeability of membranes
-Therefore– the absorption of almost all drugs would be faster from small intestine than from stomach (even for weak acids)
-Bottom line: we use pH-partition hypothesis for guideline only rather than trying to predict accurately the drug absorption
Transporters in absorption in drugs
-Many epithelial transporters now known
-Saturable: limited number of transporters per cell
-Absorption Windows: specific ligands taken up in specific parts of gut
-Play a significant role in transport of ionic compounds
-Efflux transporter p-glycoprotein: mostly for lipophilic/amphiphilic compounds
-Passive = facilitated diffusion (passive but selective pores): down the concentration gradient
-Active = due to energy expenditure of -ATP: up the concentration gradient
-Co-Transport: Can be symport i.e. in the same direction as drug transport or antiport, i.e. in the opposite direction to drug transport
ONE NOTE
What is a P-glycoprotein?
P-glycoprotein is an ATP-dependent transporter that is capable of transportation of an extremely wide variety of drugs OUT of the cell
Describe P-Glycoprotein (Efflux transporter)
-P-glycoprotein is one of the most important barriers in intestinal absorption of drugs that are substrates to p-glycoprotein
-Most of P-glycoprotein substrates are lipophilic or amphiphilic
-P-glycoprotein is expressed not only in the intestinal epithelium, but also in liver, brain, adrenal gland and kidney
-P-glycoprotein is highly expressed by some cancer cells and is responsible for “multi-drug resistance” of cancer cells
-P-glycoprotein action appears to work in concert with CYP450 3A4 (will be discussed in Metabolism section).
Which molecules 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
Which molecules will have problems to penetrate the enterocyte barrier?
-Large
-Hydrophilic
-Ionised
-Substrate to P-glycoprotein
-Substrate to metabolising enzymes in the intestinal wall
-Not a substrate to influx transporter
Describe the uptake of macromolecules and particles
-Membrane transport by diffusion or by transporters is only feasible for small molecules. Macromolecules and particles will not be absorbed this way.
-Macromolecules and particles are internalized by a process called endocytosis
-Pinocytosis (receptor-mediated or not) – macromolecules; Phagocytosis – particles up to about 1-2µm
ONE NOTE
Describe uptake of particles from GIT-Peyer’s pathes
-M-cells sample the particles from GIT for antigens and present them to underlying T and B lymphocytes
-The particles are then transported to the systemic circulation through the lymphatic system
-The amount of material that can be transported via this route is VERY low (much less than 1% of a dose)
-However, this pathway can be important in oral vaccination
ONE NOTE
