Lymphatic Transport of Drugs

Question 1

List THREE major functions of the lymphatics system.

Answer 1

1. Organisation and trafficking of immune cells
   
   1. Lymphocytes survey parts of body/organs for infection
   2. Then they drain back via the lymphatics system
2. Drainage of proteins & particulates (cellular debris, microbes, etc) from interstitial space
   
   1. ​Acts to collect & clean up things form the blood’s materials left in the interstitial space and bring to lymph nodes (that’s why lymph nodes swell durin infection).
   2. But, can also help metastasis of cancer
3. Absorption and transport of dietary lipid
   
   1. From the gut straight to the systemic circulation via intestinal lymphatic system

Question 2

Name the TWO types of lymphatics and their roles.

Answer 2

1. Intestinal lymphatics
   
   1. ​Absorption of dietary lipids (and some drugs)
   2. Direct drainage via lymph to systemic circulation (avoids first-pass metabolism)
   3. Potential to enhance bioavailability via reduction in first pass metabolism
2. Peripheral lymphatics
   
   1. ​Key role in absorption of macromolecules
   2. Potential targeting to immune cells and tissues, and to sites of metastases

Question 3

What is the significance of the structural differences between the vascular endothelium & lymph endothelium?

Answer 3

• Vascular endothelium:
  
  • Characterised by tight junctions b/w basement membranes
    
    • Difficult for bigger molecules to pass through
• Lymph endothelium:
  
  • ​Characterised by large intercellular junctions
    
    • _​_Allows access (permeability) of macromolecules or colloids that cannot cross vascular endothelium

Question 4

What quantifying factor determines the absorption of macromolecules (such as protein) into the peripheral lymphatics? Why?

Answer 4

The Molecular Weight.

Increasing protein MW increases its drainage into the lymph.

Above 25-30 kDa = lymphatics becomes the major route of absorption.
This allows us to manipulate drugs that act on WBC in lymp by increasing its size (e.g. add polymer chains) to force it into the lymph.

Question 5

How is drug normally administerd and transported into the peripheral lymphatics?

Answer 5

Parenteral administration (usually Subcutaneous).

Question 6

What are two candidates as a delivery system for peripheral lymphatic?

Answer 6

• Biological delivery system
• Colloidal delivery system

Question 7

What is the major transport pathway for lipids into the blood circulation?

Answer 7

Intestinal Lymphatic system.

Question 8

What is an advantage of intestinal lymphatic drug transport?

Answer 8

• Avoidance of first-pass hepatic metabolism
• Avoidance of enterocyte-based metabolism

Question 9

What TWO things are required for intestinal lymphatic drug transport?

Answer 9

1. Source of food/lipids (co-administered)
   
   1. To stimulate the endogenous lipid pathway
2. Highly lipophilic drug
   
   1. ​Log D > 5
   2. Triglyceride solubilty > 50 mg/mL
   3. To be able to be absorbed

Question 10

Describe lipid transport into intestinal lymph

Answer 10

1. TG is digested by lipases to smaller lipids (fatty acids & monoglycerides) to permeate into the enterocyte from the GI lumen.
2. Monoglycerides & Fatty Acids are resynthesised to TG for storage puposes.
3. TG are assembled into lipoproteins (HDLs, LDLs, VLDLs) to allow transportation around the body (since TG is poorly water soluble)
4. LP are released into the lamina propria (underlying of cell)
5. LP have poor access to the vascular endothelium due to their size and tight junctions of the vascular endothelium cells.
6. LP then are preferentially transported to the lymphatic endothelium

Question 11

Describe Drug Transport into the Intestinal Lymph.

Answer 11

1. Drug is easily absorbed into the enterocyte from the GI lumen.
2. If the drug is highly lipophilic:
   
   1. ​Drug associates with lymph lipoproteins (lipid, hence the lipophilicity) in the enterocyte
   2. Then, it is transported across into the Lamina Propria and preferentially absorbed into the intestinal lymphatic system.
3. If the drug is NOT highly lipophilic:
   
   1. _​_Drug is then transported and absorbed into both the vasuclar endothelium (preferentially) and ​intestinal lymphatic endothelium

Question 12

“If the drug is not highly lipophilic, then it will have higher affinity for the vascular endothelium, than the intestinal lymphatic endothelium.” True or False. Explain.

Answer 12

False.

The drug still has the same affinity for both vascular and intestinal lymphatic endothelium.

But the drug will still have easier transport into the vascular endothelium because:

1. Of smaller molecular size
2. Blood has a higher flow rate through the gut
   
   1. Thus, transport rate is higher = easier to carry drug away

Question 13

“Drugs require both a high log D and high lipid solubility to drive drug access (by partitioning) into the lipoprotein core for drug association with intestinal lipoproteins.” True or False. Discuss.

Answer 13

True.

Intestinal lymphatic transport is only likely for highly lipophilic drugs (high lipid solubility) that partition readily (high log P) into lipoproteins. Therefore, BOTH factors is a must.

Generally, a log D >5 & TG solubility > 50 mg/mL

Question 14

What are two requirements of a lipid source for good Intestinal Lymphatic Transport

Answer 14

1. Must be co-administered with the drug
   
   1. Helps stimulate lymphatic transport of drugs by stimulating lymphatic transport of lipids to form lymph lipoproteins.
2. Long lipid chain
   
   1. High lipophilicity (TG solubility > 50 mg/mL)
   2. The longer the chain, the greater the transport into the intestinal lymphatics.
   3. Can’t be too short, otherwise it will get absorped into the vasculare endothelium as well.

Question 15

What are TWO potential benefits that Lymphatic transport offers for drug delivery

Answer 15

1. Improvements in bioavailability
2. Potential for drug targeting

Question 16

“Access to the periphery & intestinal lymphatics in the intersitial space are both via size filtering.” True or False. Discuss.

Answer 16

True.

Possible access in periphery (via macromolecules) or intestinal submucosa (via lipoproteins)