Liver blood flow

Drug administration via the oral route Gut mucosal blood flow Liver blood flow... 

FIGURE 5.38 Pictorial presentation of the microscopic structure of the liver. The picture shows the classical liver lobulus. The functional acinus and its three zones are at the left. The acinal zones are marked by numbering them 1-3. These zones correspond to the direction of blood flow from the portal arteries (PA) to the terminal veins (TV). Zone I corresponds to the periportal area in classical liver pathology, zone 2, the interlobular region (midzone), and zone 3, centrelobular region. ... 

A special case for reduced bioavailabilty results from first-pass extraction that sometimes might be subjected to saturable Michaelis-Menten absorption kinetics. The lower the hepatic drug clearance is (Clhep) in relation to liver blood flow (Ql), or the faster the drug absorption rate constant (Ka), and the higher the dose (D) are, the more bioavailable is the drug (F). 

Decreased liver blood flow decreased liver mass... 

Data from both in vivo and in vitro systems showed PbTx-3 to have an intermediate extraction ratio, indicating in vivo clearance of PbTx-3 was equally dependent upon liver blood flow and the activity of toxin-metabolizing enzymes. Studies on the effects of varying flow rates and metabolism on the total body clearance of PbTx-3 are planned. Finally, comparison of in vivo metabolism data to those derived from in vitro metabolism in isolated perfused livers and isolated hepatocytes suggested that in vitro systems accurately reflect in vivo metabolic processes and can be used to predict the toxicokinetic parameters of PbTx-3. 

Iturriage, H., Ugarte, H. and Israel, Y, (1980). Hepatic vein oxygenation, liver blood flow and the rate of ethanol metabolism in recently abstinent alcoholic patients. Eur. J. Clin. Invest. 10, 211-218. 

Kessler, B.J., Liebler, J.B., Bronfin, G.J. and Sass, M. (1954). The hepatic blood flow and splanchnic oxygen consumption in alcoholic fetty liver. J. Clin. Invest. 33, 1338-1345. 

Hepatic reperfusion injury is not a phenomenon connected solely to liver transplantation but also to situations of prolonged hypoperfusion of the host s own liver. Examples of this occurrence are hypovolemic shock and acute cardiovascular injur) (heart attack). As a result of such cessation and then reintroduction of blood flow, the liver is damaged such that centrilobular necrosis occurs and elevated levels of liver enzymes in the serum can be detected. Particularly because of the involvement of other organs, the interpretation of the role of free radicals in ischaemic hepatitis from this clinical data is very difficult. The involvement of free radicals in the overall phenomenon of hypovolemic shock has been discussed recently by Redl et al. (1993). More specifically. Poll (1993) has reported preliminary data on markers of free-radical production during ischaemic hepatitis. These markers mostly concerned indices of lipid peroxidation in the serum and also in the erythrocytes of affected subjects, and a correlation was seen with the extent of liver injury. The mechanisms of free-radical damage in this model will be difficult to determine in the clinical setting, but the similarity to the situation with transplanted liver surest that the above discussion of the role of XO activation, Kupffer cell activation and induction of an acute inflammatory response would be also relevant here. It will be important to establish whether oxidative stress is important in the pathogenesis of ischaemic hepatitis and in the problems of liver transplantation discussed above, since it would surest that antioxidant therapy could be of real benefit. 

The portal vein is the primary vessel leading into the liver it receives deoxygenated venous blood flow from the small intestine, stomach, pancreas, and spleen (Fig. 19-1). The inflow from these organ systems accounts for approximately 75% of... 

Portal hypertension is a consequence of increased resistance to blood flow through the portal vein. Increased resistance is usually due to restructuring of intrahepatic tissue (sinusoidal damage) but may also be caused by presinusoidal damage such as portal vein occlusion from trauma, malignancy, or thrombosis. A third (and the least common) mechanism is outflow obstruction of the hepatic vein. This latter damage is posthepatic, and normal liver structure is maintained. This chapter will focus on portal hypertension caused by intrahepatic damage from cirrhosis. 

O The acute leukemias are diseases of bone marrow resulting from aberrant proliferation of hematopoietic precursors. The hallmark of these malignancies is the leukemic blast cell, a visibly immature and abnormal cell in the peripheral blood that often replaces the bone marrow and interferes with normal hematopoiesis. These blast cells proliferate in the marrow and inhibit normal cellular elements, resulting in anemia, neutropenia, and thrombocytopenia. Leukemia also may infiltrate other organs, including the liver, spleen, bone, skin, lymph nodes, and central nervous system (CNS). Virtually anywhere there is blood flow, the potential for extramedullary (outside the bone marrow) leukemia exists. 

Metabolism J. Hepatic blood flow J. Liver size J. Phase I metabolism 1 Incidence liver dysfunction T t /2 hepatically extracted drugs... 

The liver is the largest internal organ, weighing about 1.5 kg (3.3 lb) in the adult. The blood flow to the liver is 1350 ml/min (27% of the cardiac output) on average and comes from two sources ... 

The hepatic artery supplies the liver with 300 ml/min of oxygenated blood from the aorta. The remaining 1050 ml/min of blood flow is delivered by the hepatic portal vein. This blood comes directly from the digestive tract. It is low in oxygen but contains a high concentration of nutrients absorbed from the intestines. 

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 drawback of this approach is that it is essentially empirical, and does not allow for differences in metabolic clearance between the species, i.e., it assumes that clearance is proportional to blood flow. This works well for compounds that are highly extracted in the liver, and/or where passive renal clearance is the major pathway [5, 68]. An approach for compounds that are actively secreted into the urine has also been proposed [69], although the precise values of some of the physiological scaling factors have been questioned [70]. 

In man, the oral bioavailability of UK-224,671 is less than 10% [39]. Since clearance of UK-224,671 is low relative to liver blood flow, the poor oral bioavailability is due to incomplete absorption of the compound from the GIT. Caco-2 flux experi-... 

Spontaneous bacterial peritonitis (SBP) is a serious complication of cirrhotic ascites, arising most frequently in those with advanced liver disease. Its development leads to a further reduction in the effective arterial blood volume, and it has a mortality rate equivalent to that of a variceal bleed [202], Since hepatic blood flow and func-... 

It was determined that 9.5% of an oral 80-mg dose of verapamil was absorbed in a 70-kg test subject. However, because of extensive bio transformation during its first pass through the portal circulation, the bio availability of verapamil was only 25%. Assuming a liver blood flow of 1500 mLAmin, the hepatic clearance of verapamil in this situation was... 

Lockwood, A. H., Yap, E. W. H. and Wong, W. H. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. /. Cereb. Blood Flow Metab. 11 337-341,1991. 

---