LYMPHATIC TRANSPORT OF DRUGS

By U.Ashok Kumar, Trinity College of Pharmaceutical Sciences, Peddapalli, Peddapalli, A.P. India

INTRODUCTION Lymphatic vessels distributed throughout the vascular regions of the body. body. Primary Functions: Functions: 1. To drain the capillary beds and return extracellular fluid to the systemic circulation 2. The intestinal lymphatic system is responsible for the transport of dietary fat and lipid soluble vitamins to the systemic circulation. circulation. 3. Drug transport via the intestinal lymphatics may be utilized to prolong the time course of drug delivery to the systemic circulation. circulation.

4. B- and T-lymphocytes present in relatively high

concentrations compared with systemic blood. blood. 5. Specific delivery of anti-infective or anti-viral agents as antiantiin the case of HIV. HIV. 6. Targeted delivery of antitumor drugs

FLOW OF LYMPH
Lymph capillaries

Lymph Intestinal lymphatics The thoracic lymph duct The left internal jugular vein Systemic circulation
(Drug transport via Intestinal Lymphatics: Bypass first pass metabolism.)

Schematic description of the major steps involved in lipid digestion and intestinal lipoprotein synthesis. synthesis.

PREDICTION OF THE POTENTIAL FOR LYMPHATIC DRUG TRANSPORT Absorption of highly lipophilic drugs
Probucol (antihyperlipidemic) antihyperlipidemic) Cyclosporins(Immunosuppressive agent) Cyclosporins(Immunosuppressive Naftifine(antifungal) Naftifine(antifungal) Mepitiostane(anabolic steroid) Lipophilic vitamins and vitamin derivatives Halofantrine(antimalarial) Halofantrine(antimalarial) DDT: dichloro diphenyl trichloro ethane (Pesticide)

The majority of lymphatically transported drugs are associated with the TG core of the chylomicron. chylomicron. A drug should have a log partition co-efficient co(log P) in the region of 5 and Triglyceride solubility of atleast 50mg/ml. 50mg/ml.

Assessment of intestinal lymphatic transport

Animal Models(rat, dog & pig): estimate both the extent of lymphatic transport, as well as the extent of portal blood absorption( overall bioavailability)

Promotion of intestinal lymphatic drug transport

A. Prodrug approaches for enhanced

lymphatic delivery: The design of lipophilic prodrugs is a logical approach for the enhancement of lymphatic transport. Synthesis of simple esters by condensation with long chain fatty acids.

1. Simple ester / ether prodrugs:  Eg: Testosterone(oral Bioavailability is only 4% due to Eg: Presystemic matabolism.): its esterform Testosterone matabolism.): undecanoate: undecanoate: 7% Bioavailability(almost 2-fold increase in 2oral BA is condsiderable.) condsiderable.)
 The fat soluble vitamins (A, D, E and K) : Major problems associated with these formulations: Low absorption and chemical instability. Aliphatic esters improve stability and enhance absorption and lymphatic transport.  Indomethacin----- indomethacin farnesil (An aliphatic ester Indomethacin----prodrug )  Effective systemic indomethacin delivery (12% lymphatic delivery)  Reduced gastrointestinal irritation.

Epitiostanol is an antimammary tumour agent(Admin. agent(Admin. By i.m .route : Extensive First pass metabolism) Mepitiostane, 17Mepitiostane, a 17- methoxycyclopentane ether derivative of Epitiostanol shows enhanced oral bioavailability. bioavailability.

Design of Lymph directing Prodrugs: To enhance concentrations of parent drug in the systemic circulation (by avoiding first pass metabolism) To enhance concentrations of parent drug in the lymphatics for the purposes of site specific delivery. delivery.

PRODRUGS DESIGNED TO INTEGRATE INTO LYMPHATIC BIOCHEMICAL PATHWAYS

Functional approach is to integrate the prodrug into a biochemical pathway associated with lipid processing. processing. Integration into a metabolic path-way effects pathimmobilization of the molecule within the lipid digestion circumventing the absorption sink provided by the portal blood. blood. A common approach has been the synthesis of glyceride based prodrugs to target the lymphatic transport pathways of triglycerides
Melphalon, niclosamide, naproxen, L-Dopa & Chlorambucil Melphalon, niclosamide,

The use of monoglyceride or triglyceride mimics, and more recently phospholipid mimics, appear to hold promise for selective lymphatic delivery. delivery.

FORMULATION APPROACHES FOR ENHANCED LYMPHATIC DELIVERY

Choice of lipid/formulation:
Co-administered lipid determines the extent of Colympahatic absorption. The lymphatic transport of retinol and cholesterol is enhanced when administered in a micellar formulation compared with an emulsified formulation. formulation. The lymphatic transport of -tocopherol is enhanced after administration in a lecithin/medium chain triglyceride mixed micellar formulation compared with a simple lecithin micellar solution

Recent Examples
Emulsion formulations stabilized by milk fat globule membrane (MFGM) have been described for the enhancement of the intestinal lymphatic transport of vitamin D3, epidermal growth factor, vitamin A and insulin. insulin. The lymphatic transport of a lipophilic antimalarial, Halofantrine antimalarial, (Hf), has recently been studied in anaesthetised rat model. Hf),
lymphatic transport of Hf free base, formulated as a lipid

solution (2: 1 molar ratio of oleic acid:glycerol monooleate) was significantly higher than that of a acid: monooleate) suspension of Hf.HCl co-administered with the same lipid load. Hf. coload.

(Hf. (Hf.HCL solubility 1mg/Ml, Hf free base 200 mg/ml.) mg/ml.

Lymphatic drug transport in the absence of co-administered lipid coRetinyl palmitate without co-administered colipids compared with lipid solution formulation (2-fold enhancement seen). seen). Cyclosporins( Cyclosporins(5-10 fold enhancement of BA) when compared with co-admin. Lipids co-admin.
These data suggest that the co-administration of lipid cofor appreciable lymphatic drug transport may need to be re-examined. re-examined.

Propranolol: Propranolol: A Moderately lipophilic drug

Formulation containing oleic acid and propranolol 80 mg (HALOTM) with the commercial sustained release propranolol formulation (Half-inderal LA@, 80 mg) revealed a statistically (Halfsignificant doubling of the mean plasma AUC values after administration of the bile salt/oleic acid based formulation. formulation. Log P value: 3.26 value:

Conclusion
The drug delivery opportunities provided by drug transport via the intestinal lymphatics include:
Increased bioavailability via a decrease in hepatic first pass metabolism. The ability to specifically target drugs to regions of the lymphatics supplied by mesenteric lymph. A modulation in the rate of drug input to the systemic circulation thus providing an opportunity for sustained release

Prodrugs(Ether/ Prodrugs(Ether/ Ester/ Mimic molecular structures) Recent data suggests that co-administration of lipid may conot be an absolute pre-requisite for lymphatic drug pretransport, and that lipophilic drugs may partition into endogenous lymphatic lipid turnover if administered in a suitable solubilised formulation. formulation. Enhancement of lymphatic transport via formulation approaches may provide improvements in the relative bioavailability of compounds with very low absolute oral bioavailability. bioavailability. the ability to target anti-infectives, antiviral or anti-infectives, immunomodulatory agents specifically to the lymph holds considerable promise for the improved treatment of immune disease including HIV. HIV.

References
Chistopher J.H Porter, William N. Charman Intestinal lymphatic drug transport :an update Advanced drug delivery reviews 50(2001) 61-80. 50(2001) 61-80. Natelite L. Trevaskis, William N. Charman, Christopher J.H Trevaskis, Charman, Porter lipid-based delivery systems and intestinal lymphatic lipiddrug transport: Amechanistic update. Advanced drug transport: update. delivery reviews 60(2008) 702-716. 60(2008) 702-716. Chistopher J.H Porter, William N. Charman Uptake of drugs into the Intestinal lymphatics after oral administration Advanced drug delivery reviews 25(1997) 71-89. 25(1997) 71-89.