Gastrointestinal Absorption Lecture 2 Flashcards
Describe the process of oral drug administration?
- Disintegration and dissolution (luminal degradation)
- Diffusion through GI fluids
- Membrane permeation, active transport (travel through efflux pump and uptake) (metabolism in enterocytes)
- Uptake into portal vein blood headed to the liver (First pass hepatic extraction)
- Onwards to systemic circulation, binding to albumin
What are the 5 barriers to GI drug absorption?
- Lumen
- Mucous membrane
- Not properly crossing membrane: bile salts change charge so drug cannot cross
- Metabolism before the drug reaches the plasma:
- Diseased states that can effect each of the above barriers
Describe the chemical degradation involved in the lumen that acts as a barrier?
- pH in the stomach when fasted or fed
- Drug stability often affected by pH
- Drugs such as erthyromycin, methypenicillin and omeprazole depend on the pH to metabolise them
- Enteric coated tablets can be used to bypass the stomach and prevent gastric irritation
Describe the enzymatic degradation involved in the lumen that acts as a barrier?
- Stomach: pepsin which will cleave amino acids such as cyclosporin
- Small intestines: lipases, amylases and proteases
- Stimulated by presence of food - Drugs which resemble nutrients will be cleaved by these enzymes
- Colon has many bacterial enzymes that cleave molecules: sulfazalzine is broken down to treat ulcerativie colitis
Describe the complexation involved in the lumen that acts as a barrier?
- Lifestyle factors: Milk and antacids neutralise the effect of tetracycline
- Secretions: Bile salts stimulated by food, generally solubilise poorly water soluble drugs
- Can also form insoluble complexes with drugs such as nystatin
Describe the adsorption involved in the lumen that acts as a barrier?
- Drug can bind to food molecules due to ions having high energy
- Rarely happens, however, charcoal is used to absorb toxins
Describe the two separate structures of the mucus layer?
- One firmly attached to the endothelial cells
2. One loosely attached that can slough off and transit with/lubricate food
Describe how drug absorption may be effected by the mucus?
- Has to cross the mucous to reach the membranes
2. If high viscosity of mucous there is less absorption
Describe the functions of the epithelial cells and where they are found in the small intestine?
- Found on the basal membrane that are joined together by tight junctions (contains brush border)
- They express:
- ABC transporters: efflux cells back into lumen
- Cytochrome P450 enzymes: metabolise some drugs
Explain the transcellular route of absorption through the GIT?
Major route of absorption
- Passive diffusion: no energy needed
- Ficks law: concentration gradient driven, dependent on partition co-efficient
- Apical membrane phospholipid: lower permeability than basolateral membrane
- Molecules partition and diffuse into membrane and interior to reach basolateral membrane
Explain the paracellular route of absorption through the GIT?
- Absorption by travelling through tight junctions between cells
- Moderately sized molecules
- Passive diffusion mechanism
- Generally for molecules like Ca2+, amino acids
Explain the carrier mediated route of absorption through the GIT?
- Between many transporters (proteins) in apical cell membrane
- Examples:
- Peptide, nucleotide, sugar, amino acid, bile - Drug properties that are similar to natural substrates are binded and carried through apical membrane AGAINST concentration gradient
Define what transcytosis is?
Vesicle with internalised material is transported through to the other side of the cell and secreted on the opposite basolateral cell
Describe the function of counter transport efflux proteins?
- Highly expressed on apical membrane
- Efflux (re-transport) back into the lumen
- Nifedipine
Describe the pre systemic circulation?
- Starting from the stomach/intestines/colon, drug travels from the hepatic portal vein to the liver before reaching systemic circulation
- Cytochrome P450 metabolism
