Absorption of Lipid + Lymphatic System Flashcards
What are the different mechanisms of intestinal lymphatic transport of drug following oral administration?
What is the main mechanism?
- Micro/nanoparticles via Peyer’s patches (minor)
- Very large water-soluble macromolecules that are too large to penetrate blood capillary (rare)
- Lipophilic drugs in association with chylomicrons (large lipoproteins that are assembled in the enterocyte in the presence of dietary lipids) (IMPORTANT)
What is the most important function of intestinal lymphatic system?
Absorption of dietary lipids
Describe luminal digestion of dietary lipids
The lipid emulsion enters the small intestine from stomach as fine lipid droplets that are less than 0.5 µm in diameter.
Bile salts and pancreatic fluids are secreted in response to the lipids.
Biliary lipids bind to the surface of the emulsified lipid and improving colloidal stability and reducing particle size.
Digestion of triglycerides is mostly due to the _____ at the interface between the oil and aqueous phases in the upper part of the intestinal lumen.
Pnacreatic lipase
TG lipid droplets covered with bile acids are _____ to pancreatic lipase.
The binding of the ______ to the triglyceride/aqueous interface allows the lipase molecule to bind to the lipid/aqueous interface.
Not accessible
Co0lipase
Which parts of the triglyceride molecule does pancreatic lipase act on?
Acts on sn-1 + sn-3
This is to release one molecules of 2-monoglyceride + molecules of free fatty acids
The amphiphilic products of digestion of triglycerides in the presence of bile salts and phospholipids form what?
Different colloidal structures including multilamellar and unilamellar vesicles, as well as mixed bile salt-lipid micelles
The micellar solubilisation of monoglyceride and fatty acids greatly enhances the number of molecules available for uptake by the enterocytes
How do fatty acids cross the membrane of the enterocyte?
At low fatty acid concentrations: fatty acids are taken up via a transporter dependent process
At high fatty acid concentrations (after a meal), fatty acids are taken up by passive diffusion
Fatty acid binding proteins (FABPs) bring _____ fatty acids (> 12 carbons) to _____, where triglyceride re-esterefication occurs.
_____ fatty acids (< 12 carbons) generally diffuse across the enterocyte and directly enter the blood capillaries that supply the _____.
Long-chain
Smooth endoplasmic reticulum
Short + medium
Portal Vein
Where does re-esterification occur?
Smmoth endoplasmic reticulum
Triglyceride synthetase is located at the cytoplasmic surface of SER which triglycerides are formed
Triglycerides have low solubility in phospholipid bilayers, so triglycerides saturate the membrane rapidly and form droplets
What happens in the rough ER?
What is formed in the rough ER?
Process of formation of primordial lipoproteins
Synthesis of apoprotein-B in the rough ER + its association with phospholipids present in membrane
Addition of small amounts of triglycerides apoprotein-B-phospholipid complex.
What are the 2 most important conditions for intestinal lymphatic transport of lipophilic drugs?
The drug should to able to associate with chylomicrons in the enterocyte
The drug has to be co-administered with high-fat meal or with lipid-based formulation that contains long-chain triglyceride or long-chain fatty acids
What physicochemical properties of drugs are important for lymphatic transport?
LogP > 5
High triglyceride solubility (> 50 mg/g)
Lymphatic transport can increase significantly the _____ of lipophilic drugs
Oral bioavailability
_____ are transported by the intestinal lymphatic system after oral administration
Lipid-soluble vitamins (A, D, K, E)
