What determines if a compound is primarily taken up by the lymphatic extensions rather than the portal vein blood supply in the intestinal villi?

Question

I am currently studying the intestinal absorption/transport systems, but am confused about one part specifically. There are hydrophilic and lipophilic compounds (to varying degrees), and they get absorbed by different methods.

As far as I can tell there are 3 main ways of absorption in the intestinal wall:

1. Passive diffusion of lipophilic compounds through the membrane.
2. Passive diffusion of hydrophilic compounds through pores and gap junctures.
3. Active transport of larger molecules by transport proteins.

But once a compound passes the enterocyte absorption cells in the lining of the villi of the intestine, there are primarily two paths into systemic circulation:

1. Capillaries of the blood supply from the hepatic portal vein, leading to the liver and first pass metabolism.
2. Lymphatic uptake through the extension of the intestinal lymph system in there.

From what I can tell anatomically, both of these are somewhat intertwined/overlapped to an extend — but which properties of a compound determine whether it is primarily taken up by the lymph system (getting it to the blood supply eventually circumventing first pass hepatic metabolism) or wether more of it is taken up by the local portal vein capillaries? Is it small differences outside of the general hydro/lipophilic nature like size etc.?

Please correct me if I'm misunderstanding some of these basic anatomic concepts. I would appreciate if someone can tell me whether there is a set of parameters involved in this biochemical branching.

I just read the lacteals, the lymphatic vessels in the villi, absorb digested fats. Does that mean the more lipophilic a compound is the more likely it is to be absorbed by the lymph over the portal vein capillaries? That sounds a bit too simple for me. There must be more factors involved.

Answer 1

The path used for a particular compound is determined by several factors:

Affinity for Plasma Proteins: Compounds with a high affinity for plasma proteins are more likely to remain in the bloodstream rather than diffusing into the lymphatic system.

Lipophilicity: Highly lipophilic compounds are more likely to be absorbed into the lymphatic system because they can be incorporated into chylomicrons, which are too large to pass through the capillaries of the blood supply and thus enter the lacteals.

Molecular Size: Larger molecules, especially those larger than the fenestrations in the capillary endothelium, are more likely to enter the lymphatic system for the same reason as above.

Solubility: Compounds that are not water-soluble may need to be transported in association with bile acids or incorporated into micelles to be absorbed. After absorption they are often repackaged into chylomicrons and enter the lymphatic system.

Transport Mechanisms: Some compounds require active transport mechanisms to cross the intestinal epithelium. These mechanisms can be selective and influence whether a substance enters the blood or the lymphatic system after absorption.

Chemical Stability and Metabolism: Some compounds may be metabolically unstable in the gastrointestinal tract or the liver. If they are metabolised in the enterocytes, the metabolites may have different properties that affect their route of absorption.

Charge/Ionisation State: The ionisation state can affect the compound's ability to cross the lipid-rich cell membranes. Non-ionized (lipophilic) forms are more likely to be absorbed through the lymphatic system, while ionized forms are generally more hydrophilic and absorbed into the portal circulation.

Formulation: The pharmaceutical formulation of a compound can influence its absorption. For example, lipid-based formulations may enhance lymphatic uptake of certain drugs.

Note that these paths are not mutually exclusive. The relative contribution of each factor varies with the specific properties of the compound in question. The extent to which each path is used can vary greatly and is influenced by these factors, and of course this implies that a molecule may use both paths, and this is determined by metabolites utilising different pathways, partial absorption by both routes, regional absorption variations and variable physiological conditions