LYMPHATIC TRANSPORT OF D RUGS

1. LYMPHATIC TRANSPORT OF DRUGS Avinash Kodoori Mpharm (Pharmceutics) II semester Department of Pharmaceutics Uniiversity College of Pharmaceutical Sciences Kakatiya University Warangal

2. Contents • Role of the lymphatic system • Organisation of Lymphatic system • Formation of Lymph • Fat absorption • Advantages of intestinal lymphatic drug transport • Enhancing Lymphatic Transport • Prodrugapproaches • Formulation approaches • Conclusion

3. Role of The lymphatic system • 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

4. 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

5. Lipid absorption: • In the small intestine, special lymphatic vessels called lacteals absorb dietary lipids that are not absorbed by the blood capillaries

6. Organisation of Lymphatic system Lymphatic capillaries Lymphatic vessels Lymph nodes Collecting ducts

8. Lymphatic capillaries: • slightly larger than blood vessels • Have a unique one way structure that permits interstitial fluid to flow into them but not out

11. 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.

13. 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.

14. Functions of a lymph node: • filter the lymph • assist bone marrow and the thymus in the production and maturation of lymphocytes • assist in getting an immune response going

15. Lacteals: • Specialised lymphatic capillary • Present in the villi of the small intestine. • It absorbs dietary fats

16. Why Lymph forms? • Fenestrated blood capillaries 20-100 nm • RBC 6-8μm = 6000-8000 nm • Lymphatic capillaries 50-500 nm upto 1000 nm

19. Absorption of Fats • Emulsification by lecithin and bile acids • Fat hydrolysis by lipases to leave mono glycerides

20. Micelle formation by aid of bile acids • Chylomicronformation in enterocytes

21. Uptake of Chylomicrons into lymph

23. 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),

24. Advantages of intestinal lymphatic drug transport • 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

25. Avoidance of hepatic first pass metabolism First Pass Effect

26. Selective treatment of diseases and infections of the mesentric lymphatic • Elephantiasis occurs in the presence of microscopic, thread-like parasitic worms of • Wuchereriabancrofti, • 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.

27. Lymph and Cancer metastasis T N M • TNM Classification of Malignant Tumours (TNM)

28. Sustained drug action Blood flow : Lymph flow 500:1

29. Enhancing Lymphatic Transport • A log octanol/water partition coefficient i.e, Log P> 5 • Soluibilty in lipids atleast50 mg/ml 33.5% 2.3%

30. Methods to improve lymphatic transport • Prodrug approaches • Formulation approaches

31. 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.

32. 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 formulations • low absorption and • chemical instability. • Aliphatic esters have been synthesised to improve stability and to enhance absorption and lymphatic transport

33. 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

34. 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.

36. 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.

37. Chlorambucil(3.4% via lymph) • treatment for Hodgkins & lymphoma • Significant oral bioavailability • Chlorambucildiglyceride – (26% via lymph) • Used to target lymph

38. Formulation approaches • Co administered lipid stimulates lipid turnover; thereby increasing the lipoprotein-based lipid sink into which drugs partition • Also by • Increased solubilisation in Intestine • Reducing gastric emptying • Incresase mucosal permeability

39. 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

40. 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-C10fatty acids)

41. 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

42. Conclusion • 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

43. References • Harper’s Illustrated Biochemistry, 26thedition,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. CharmanIntestinal lymphatic drug transport :an update Advanced drug delivery reviews 50(2001) . • Chistopher J.H Porter, William N. CharmanUptake 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