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LYMPHATIC TRANSPORT OF D RUGS. Avinash Kodoori Mpharm (Pharmceutics) II semester. Department of Pharmaceutics Uniiversity College of Pharmaceutical Sciences Kakatiya University Warangal. Contents. Role of the lymphatic system Organisation of Lymphatic system Formation of Lymph - PowerPoint PPT Presentation
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Avinash KodooriMpharm(Pharmceutics)II semesterDepartment of PharmaceuticsUniiversity College of Pharmaceutical SciencesKakatiya UniversityWarangal
1. Role of the lymphatic system2. Organisation of Lymphatic system3. Formation of Lymph4. Fat absorption5. Advantages of intestinal lymphatic drug
transport6. Enhancing Lymphatic Transport
a) Prodrug approachesb) Formulation approaches
7. Conclusion
Fluid recovery:
Fluid continually filters from our blood capillaries into the tissue spaces.
Proteins “leak” into the interstitial fluid
The blood capillaries reabsorb most of it
Each day, they lose an excess of 2 to 4 L of water and one-quarter to one-half of the plasma protein.
The lymphatic system absorbs this excess fluid and returns it to the bloodstream by way of the lymphatic vessels.
Drainage system of the body
Immunity:
As the lymphatic system recovers excess tissue fluid, it also picks up foreign cells and chemicals from the tissues.
On its way back to the bloodstream, the fluid passes through lymph nodes, where immune cells stand guard against foreign matter. When they detect it, they activate a protective immune response.
Lymphocytes
Lipid absorption:
In the small intestine, special lymphatic vessels called lacteals absorb dietary lipids that are not absorbed by the blood capillaries
Lymphatic capillaries
Lymphatic vessels
Lymph nodes
Collecting ducts
Lymphatic capillaries:
slightly larger than blood vessels
Have a unique one way structure that permits interstitial fluid to flow into them but not out
Lymph nodes:
Lymph nodes are small encapsulated organs located along the pathway of lymphatic vessels
1 mm to 1 to 2 cm in diameter
widely distributed throughout the body, with large concentrations occurring in the areas of convergence of lymph vessels.
Afferent lymphatic vessels carry lymph into the nodes where waste products and some of the fluid are filtered out
Efferent lymphatic vessels carry lymph out of the node to continue its return to the circulatory system
Lymphocytes, which are specialized white blood cells located within the lymph node, kill pathogens that may be present.
Lymph nodes also trap cancer cells and slow the spread of the cancer until they are overwhelmed by it.
Functions of a lymph node:
1)filter the lymph
2)assist bone marrow and the thymus in the production and maturation of lymphocytes
3)assist in getting an immune response going
Lacteals: Specialised lymphatic
capillary
Present in the villi of
the small intestine.
It absorbs dietary fats
Fenestrated blood capillaries 20-100 nm
RBC 6-8μm = 6000-8000 nm
Lymphatic capillaries 50-500 nm upto 1000 nm
1) Emulsification by lecithin and bile acids
2) Fat hydrolysis by lipases to leave mono glycerides
3) Micelle formation by aid of bile acids
4) Chylomicron formation in enterocytes
5) Uptake of Chylomicrons into lymph
Briefly, lipids are hydrolysed in the stomach and small intestine to the corresponding 2-monoglyceride (MG) and fatty acid (FA)
They are absorbed into the enterocyte, re-esterified into triglyceride (TG) and ‘packaged’ into intestinal lipoproteins., chylomicrons and very low density lipoproteins (VLDL),
Avoidance of hepatic first pass metabolism. Increased bioavailability Selective treatment of diseases and
infections of the mesentric lymphatic. Enhancement of absorption of large
molecules such as peptides and particulates. Targeting Inhibition of cancer cell
metastasis. Sustained drug action Transport of poorly water soluble and
highly lipophilic drug candidates
Avoidance of hepatic first pass metabolism
First Pass Effect
Selective treatment of diseases and infections of the mesentric lymphatic
Elephantiasis occurs in the presence of
microscopic,thread-like parasitic worms of
Wuchereria bancrofti, Brugia malayi, and B. timori
The adult worms live in the human lymphatic system.
Obstruction of the lymphatic vessels leads to swelling in the lower torso, typically in the legs and genitals.
Lymph and Cancer metastasis
T N M
TNM Classification of Malignant Tumours (TNM)
T N M
size or direct extent of the primary tumor
degree of spread to regional lymph nodes
presence of metastasis
0-4 0-3 0-1
Sustained drug action
Blood flow : Lymph flow
500:1
A log octanol/water partition coefficient i.e,
Log P> 5
Soluibilty in lipids
atleast 50 mg/ml
33.5%2.3%
Methods to improve lymphatic transport
◦ Prodrug approaches
◦ Formulation approaches
Prodrug approaches
The molecular and physico-chemical features of candidate compounds for lymphatic transport are restrictive due to the requirement for high lipophilicity.
Therefore, the design of lipophilic prodrugs is a logical approach for the enhancement of lymphatic transport.
Simple ester/ether prodrugs
The fat soluble vitamins (A, D, E and K) are poorly water soluble and rely on transport via the intestinal lymphatics for absorption
The major problems associated with their
formulations1) low absorption and 2) chemical instability.
Aliphatic esters have been synthesised to improve stability and to enhance absorption and lymphatic transport
Simple ester/ether prodrugs ...Epitiostanol – anti mammary tumour agent
Problems -High first pass metabolism Hence given I/M
Mepitiostane; a 17-methoxy cyclopentane ether derivative• Effective orally• Improved lymphatic transport and bioavailability
Glyceride prodrugs
integrate the prodrug into a biochemical pathway associated with lipid processing.
Integration into a metabolic path way effects immobilisation of the molecule within the lipid digestion/absorption cascade thereby circumventing the absorption sink provided by the portal blood.
L-Dopa diglyceride
L-Dopa – oral bioavailability low- Significant first pass effect- only 0.2 % via lymph
L- Dopa diglyceride- 20 % via lymph
The rationale for the prodrug is that the fatty acids in the l- and 3-positions are cleaved during lipid digestion leaving the 2-substituted L- Dopa derivative, as a 2 - monoglyceride mimic, which is absorbed and incorporated into the TG resynthesis pathway.
Chlorambucil (3.4% via lymph)
a)treatment for Hodgkins & lymphomab)Significant oral bioavailability
Chlorambucil diglyceride – (26% via lymph)◦ Used to target lymph
Formulation approaches
Co administered lipid stimulates lipid turnover; thereby increasing the lipoprotein-based lipid sink into which drugs partition
Also by
1. Increased solubilisation in Intestine2. Reducing gastric emptying3. Incresase mucosal permeability
Degree of unsaturation of administered lipid
The degree of fatty acid unsaturation have large effect on the rate of absorption and partitioning of lipids between portal blood and intestinal lymph.
lipids with increasing degrees of unsaturation appear to produce larger size lymph lipoproteins and preferentially promote lymphatic lipid transport.
Example:Lymphatic transport of testosterone undecanoate
In mono unsaturated lipid vehicle=1 X In poly unsaturated lipid vehicle =2 X
Fatty acid chain length of administered lipid
fatty acids with chain lengths of 14 and above are absorbed directly into the thoracic lymph,
shorter chain lipids are absorbed directly into the blood.
Lymphatic transport of exogenously administered increased in linear fashion after co-administration with triglycerides of increasing fatty acid chain length.
Vitamin D3
3 times More efficiently absorbed with peanut oil (C18 oleic acid) than with Miglyol (C8-C10 fatty acids)
Class of administered lipid (Structure)
Long chain fatty acid are more efficient than corresponding triglycerides
Shorter lag time Improved lymphatic transport
Because synthesis of chylo microns from Fatty acid is faster when compared to tri glycerides
2-fold increase in transport of DDT from C18 fatty acid when compared to corresponding triglyceride
Transport of orally administered drugs to the systemic circulation via the intestinal lymph may provide a number of delivery advantages including avoidance of first pass hepatic metabolism and site specific delivery to the lymphatics
Lymphatic drug transport should be considered as a possible mechanism for very lipophilic drugs.
Further the ability to target anti-infectives anti viral , immuno modulatory and anticancer agents specifically to the lymph holds considerable promise for the improved treatment of immune diseases including HIV and Cancer
Harper’s Illustrated Biochemistry, 26th edition,by Robert K. Murray
Principles of Anatomy and Physiology, 11th edition, by Tortora.
Essentials of medicinal physiology ,by K Sembulingam.
Saladin: Anatomy & Physiology: The Unity of Form and Function, Third Edition
Textbook of Medical Physiology by Guyton
Chistopher J.H Porter, William N. Charman Intestinal lymphatic drug transport :an update Advanced drug delivery reviews 50(2001) .
Chistopher J.H Porter, William N. Charman Uptake of drugs into the Intestinal lymphatics after oral administration Advanced drug delivery reviews 25(1997)
http://faculty.stcc.edu/AandP/AP/AP2pages/Units21to23/immune/lymph1.htm