Blood portal

The ammonia produced by enteric bacteria and absorbed into portal venous blood and the ammonia produced by tissues are rapidly removed from circulation by the liver and converted to urea. Only traces (10—20 Ig/dL) thus normally are present in peripheral blood. This is essential, since ammonia is toxic to the central nervous system. Should portal blood bypass the liver, systemic blood ammonia levels may rise to toxic levels. This occurs in severely impaired hepatic function or the development of collateral links between the portal and systemic veins in cirrhosis. Symptoms of ammonia intoxication include tremor, slurred speech, blurred vision, coma, and ultimately death. Ammonia may be toxic to the brain in part because it reacts with a-ketoglutarate to form glutamate. The resulting depleted levels of a-ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons. 

Garcea, G. et al.. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration, Br. J. Cancer, 90, 1011, 2004. 

Curcumin possesses strong antioxidant capacities, which may explain its effects against degenerative diseases in which oxidative stress plays a major role. As previously described for flavonoids, it is unlikely that curcumin acts as a direct antioxidant outside the digestive tract since its concentration in peripheral blood and organs is very low (near or below 1 pM, even after acute or long-term supplementation). Indeed, it has been shown that the intestinal epithelium limits its entry into the body, as reflected by absorption studies in various models (portal blood perfusion, everted bags). ... 

Fig. 24 Total amount of radioactivity absorbed during 1 hr, plotted versus portal blood flow. Ordinate absorption as a percentage of the amount infused into the duodenum. Abscissa mean portal blood flow in milliliters per minute. Each point represents one guinea pig. (From Ref. 56).

A. Haas, H. Lullman, and T. Peters, Absorption rates of some cardiac glycosides and portal blood flow, Eur. J. Pharmacol, 19, 366-370 (1972). 

Blood flowing from the intestines to the liver through the hepatic portal vein often contains bacteria. Filtration of this blood is a protective function provided by the liver. Large phagocytic macrophages, referred to as Kupffer cells, line the hepatic venous sinuses. As the blood flows through these sinuses, bacteria are rapidly taken up and digested by the Kupffer cells. This system is very efficient and removes more than 99% of the bacteria from the hepatic portal blood. 

The compound in the portal blood is transported to the liver, which usually is the major site of metabolism for pharmaceuticals. In the liver there is usually one, or more, of three principal fates for the drug either metabolism excretion into the bile or return to the blood for distribution to the other tissues of the body. These other tissues may also be sites of metabolism or, particularly in the case of the kidney, sites of excretion. 

The mesenteric blood empties into the hepatic portal vein from where it is transported to the liver. At the liver, drug and metabolites can also be extracted from the portal blood and either metabolized or excreted unchanged into the bile. This is termed hepatic first-pass extraction. 

Cirrhosis results in elevation of portal blood pressure because of fibrotic changes within the hepatic sinusoids, changes in the levels of vasodilatory and vasoconstrictor mediators, and an increase in blood flow to the splanchnic vasculature. The pathophysiologic abnormalities that cause it result in the commonly encountered problems of ascites, portal hypertension and esophageal varices, HE, and coagulation disorders. 

This can be further simplified if it is assumed that there is no accumulation of drug on the blood side (i.e. < < CJ ) or the portal blood is considered... 

Using an alternative method, generally referred to as an indirect method, Eg may also be estimated following i.d. dosing alone and sampling portal blood and the systemic circulation concurrently. The mass of drug appearing in the portal vein (Ma) is defined as follows ... 

Direct determination of portal blood flow rate is difficult and would generally require placement of an electronic flow probe in each animal. However the technique proposed by Hoffman et al. utilised tritiated water as an absorption probe (i.e. internal standard) [89], By dosing and sampling drug/ absorption probe concurrently, factors such as variable portal blood flow rate are normalised between experiments. 

Hoffman DJ, Seifert T, Borre A and Nellans HN (1995) Method to Estimate the Rate and Extent of Intestinal-Absorption in Conscious Rats Using an Absorption Probe and Portal Blood-Sampling. Pharm Res 12 pp 889-894. 

GLUT 2, a low-affinity transporter, is in hepatocytes. After a meal, portal blood from the intestine is rich in glucose. GLUT 2 captures the excess glucose primarily for storage. When the glucose concentration drops below the for the transporter, much of the remainder leaves the hver and enters the peripheral circulation. 

An important source of galactose in the diet is the disaccharide lactose present in milk. Lactose is hydrolyzed to galactose and glucose by lactase associated with the brush border membrane of the small intestine. Along with other monosaccharides, galactose reaches the liver through the portal blood. 

Fructose is found in honey and fruit and as part of the disaccharide sucrose (common table sugar). Sucrose is hydrolyzed by intestinal brush border sucrase, and the resulting monosaccharides, glucose and fructose, are absorbed into the portal blood. The liver phosphorylates frurtose and cleaves it into glyceraldehyde and DHAP. Smaller amounts are metabolized in renal proximal tubules. The pathway is shown in Figure 1-12-7 important enzymes to remember are ... 

Most of the amino acids that enter the portal blood are taken up and metabolised by the liver. Hence, some synthesis of peptides taken place in the enterocytes where there is a plentiful supply of amino acids for these processes. 

As discussed in Chapter 5, the transport of glucose into the Uver cell is near-equilibrium, so that the intracellular glucose concentration is similar to and follows precisely the changes in that of the hepatic portal blood. Fnrther-more, since it is near-equilibrium glucose can be transported into or out of the cell. 

In summary, an increase in the glucose concentration in the portal blood results in an increase in the hepatic concentration of glucose which leads to three changes ... 

Summary of the enzymes affected by an increase in the hepatic portal blood concentration and hence in the intracellular concentration of glucose in the liver... 

Medium-chain fatty acids are also present in bovine milk and some plant oils (e.g. coconut). After digestion of the triacylglycerol, they are taken up by the enterocytes in the small intestine but are not esterified. Instead they pass directly into the hepatic portal blood, from where they are taken up by the liver for complete oxidation or conversion to ketone bodies. 

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