Transport into the Lymphatic System

An additional route of uptake upon peroral administration is the passage of the M-cells of the Peyer s patches [18]. Although this route in essence has only a low transport capacity, it is of importance for mucosal (peroral) vaccination, for example. The Peyer s patches are located in the small intestine where M-cells, which neither possess a mucus nor a glycocalix layer in comparison to the adjacent enterocytes, allow the drug uptake via transcytosis. The drug is then transported into the lymphatic system and causes an immune response in the case of the vaccination approach. Absorption via M-cells in essence is possible due to the decreased enzymatic activity and their rather high permeability. 

The plasma lipoproteins include chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). They function to keep lipids (primarily triacylglyc-erol and cholesteryl esters) soluble as they transport them between tissues. Lipoproteins are composed of a neutral lipid core (containing triacylglycerol, cholesteryl esters, or both) surrounded by a shell of amphipathic apolipoproteins, phospholipid, and nonesterified cholesterol. Chylomicrons are assembled in intestinal mucosal cells from dietary lipids (primarily, triacylglycerol) plus additional lipids synthesized in these cells. Each nascent chylomicron particle has one molecule of apolipoprotein B-48 (apo B-48). They are released from the cells into the lymphatic system and travel to the blood, where they receive apo C-ll and apo E from HDLs, thus making the chylomicrons functional. Apo C-ll activates lipoprotein lipase, which degrades the... 

Transport to the liver Retinol esters present in the diet are hydrolyzed in the intestinal mucosa, releasing retinol and free fatty acids (Figure 28.19). Retinol derived from esters and from the cleavage and reduction of carotenes is reesterified to long-chain fatty acids in the intestinal mucosa and secreted as a component of chylomicrons into the lymphatic system (see Figure 28.19). Retinol esters contained in chylomicrons are taken up by, and stored in, the liver. 

TGs are packaged into chylomicrons and transported through the lymphatic system. 

The absorption of natural vitamin K from-the small intestine into the lymphatic system is facilitated by bile, as is true for other fat-soluble materials. Efibciency of absorption varies from 15% to 65% as reflected by recovery in lymph within 24 hours. Vitamins Ki and K2 are bound to chylomicrons for transport from mucosal cells to the liver. Menadione (Ks) is more rapidly and completely absorbed from the gut before entering the portal blood. In liver, intraceUular distribution is mostly in the microsomal fraction, where phenylation of menadione to form K2 occurs. Release of vitamin K to the blood stream allows association with circulating P-lipoproteins for transport to other tissue. Significant levels of vitamin K have been noted in the spleen and skeletal muscle. 

The small intestinal tract is the major place of digestion and absorption. Protein digestion reaches approximately 15% in the stomach, and in the lower intestine, the hydrolyzed fraction amounts to about 60%. Seventy percent of fats, 60% of carbohydrates, and about 30% of protein and peptide are absorbed within the duodenum. Within enterocytes, triglycerides are resynthesized from long-chain fatty acids and transformed into chylomicrons, which are transported via the lymphatic system, whereas short- and medium-chain fatty acids are directly transported into mesenteric and portal vein system. 

Together with dietary fat, both tocopherols and tocotrienols are absorbed in the digestive tract, incorporated into chylomicrons, and transported in the lymphatic system. However, following chylomicron clearance, tocotrienols disappear from circulating plasma, whereas tocopherol, especially a-tocopherol, is preferentially secreted into plasma. a-Tocopherol transfer protein, which controls plasma a-tocopherol levels, has an affinity of only 12% for a-tocotrienol (compared with 100% for a-tocopherol). The reason for the low plasma tocotrienol concentrations compared with tocopherols is the very fast clearance, as demonstrated by Yap et al. ... 

Retinol is nearly always present in the food in the form of esters which are hydrolysed in the lumen of the intestine. The retinol released is quite readily absorbed into the mucosal cells where it is re-esterified, chiefly with palmitic acid. The retinyl esters are then transported via the lymphatic system into the portal circulation from which they are removed and stored in the liver. Release of the vitamin from the liver depends on the production by the liver of a special retinolbinding protein (RBP). Production of the retinol-binding protein may be disturbed in diseases of the liver or kidneys or in protein/energy malnutrition. In such circumstances retinol cannot be mobilized from the stores and a secondary deficiency may result. Thus it can be seen that the level of retinol in the general circulation is normally highly regulated and is more or less independent of the body s reserves. 

Normally, absorbed lipids leave the mucosal cells in the form of chylomicrons which are discharged into the lymphatic system. Only short and medium chain fatty acids (up to Ciq) are carried by portal vein blood (Isselbacher 1964). In a-/3-lipoproteinemia no fat is seen in the lymphatic spaces of the small bowel (Isselbacher 1965), and no chylomicrons appear in the plasma after fat loading (see figure 5). It appears that the defect in a-jS-lipoproteinemia concerns the lipid transport from the mucosal cells into the lymphatic system. For the formation of chylomicrons, jS-lipoproteins (Isselbacher 1965), but not a-lipoproteins (Fredrickson 1966) seem to be necessary. The fat absorption defect is not improved with transfusion of normal jS-lipoproteins (Frezal et al. 1961). 

Within the villi, the chylomicron enters a lymphatic capillary called a lacteal, which merges into larger lymphatic vessels. It is transported via the lymphatic system and the thoracic duct up to a location near the heart (where the arteries and veins are larger). The thoracic duct empties the chylomicrons into the bloodstream via the left subclavian vein. At this point the chylomicrons can transport the triglycerides to where they are needed. 

Figure 7. Mixed micelles carry the solubilized hydrophobic lipids through the aqueous digest medium into close proximity with the intestinal mucosal cells (enterocytes). Micelles are not absorbed intact, but the various components are taken up by the enterocytes at independent rates. Intracellular esterification of cholesterol by acyl-coenzyme A prevents its transport back to the intestinal lumen. After esterification, cholesterol esters are assembled into chylomicrons and secreted into the lymphatic system and, finally, to the blood circulation.

By definition, chylomicrons are found in chyle formed only by the lymphatic system draining the intestine. They are responsible for the transport of all dietary lipids into the circulation. Small quantities of VLDL... 

Chylomicrons leave the absorptive cell by way of exocytosis. Because they are unable to cross the basement membrane of the blood capillaries, the chylomicrons enter the lacteals, which are part of the lymphatic system. The vessels of the lymphatic system converge to form the thoracic duct that drains into the venous system near the heart. Therefore, unlike products of carbohydrate and protein digestion that are transported directly to the liver by way of the hepatic portal vein, absorbed lipids are diluted in the blood... 

Figure 4.13 Uptake of bile acids in the jejunum. Bile adds (BA) and cholesterol (C) are secreted from the liver, via the bile, into the duodenum. Cholesterol is transported back into the blood, from the enterocyte, within chylomicrons. The latter enter the lymphatic system (i.e. the lacteals). Bile acids are absorbed from the jejunum into the hepatic portal vein for re-uptake into the liver.

Particulates can either cross into the lymphatics at the spaces in the tracheobronchial wall where epithelial cells directly overlay lymphoid tissue or pass through the endothelium of thin capillary walls in the air spaces. The transfer is a portion of a clearance mechanism that assists the lung in maintaining its normal function of gas exchange. Absorbtion and transport mechanisms of a variety of materials that enter the lymphatics continue to be studied. It was shown early in this century that water, dyes, proteins, bacteria, lipids, and particulates enter the lymphatic system relatively easily. The rates of transport and quantity vary with the size and chemistry of the material. Classic studies by Kihara (1924 1950) and Nishikawa (1941) dem-... 

A percentage of xenobiotics absorbed in the gastrointestinal cells may be biotransformed prior to entering the circulatory system the balance is transported as the parent compound. The absorbed compounds may enter the circulation either via the lymphatic system, which eventually drains into the bloodstream, or via the portal circulation, which carries them to the liver. 

The mechanism of absorption after SC or IM administration is thought to occur via the lymphatic system. The mAbs enter the lymphatic system by convective flow of interstitial fluid into the porous lymphatic vessels. The molecular mass cut-off of these pores is >100-fold the molecular mass of mAbs. From the lymphatic vessels, the mAbs are transported unidirectionally into the venous system. As the flow rate of the lymphatic system is relatively low, mAbs are absorbed over a long time period after administration. The resulting time of maximum concentration (tmax) is much later (typically 1-8 days), and the systemically available fraction (F) is equal or lower (typically 0.5-1.0) compared to the IV administration of mAbs. For example, SC injection of 40 mg adalimumab results in a tmax of approximately 5 days, and F is approximately 64%. 

The well-fed, or postabsorptive, state. After we consume and digest an evening meal, glucose and amino acids are transported from the intestine to the blood. The dietary lipids are packaged into chylomicrons and transported to the blood by the lymphatic system. This fed condition leads to the secretion of insulin, which is one of the two most... 

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