Liver metabolic capacity

Antipyrine is oxidized through biotransformation, independently of perfusion, predominantly in the micro-somes, and is excreted after hydroxylation and conjugation. After oral administration (15 or 18 mg/kg BW, respectively), the metabolic clearance ability of the liver (metabolic capacity of the microsomal monooxygenase system) can be assessed by computation of the concentration curve and the plasma half-life (after 3 and 24 hours). The serum half-life and plasma clearance are significantly enhanced/decreased, depending on the reduction in liver function. There is a close correlation with the galactose elimination capacity as well as with Quick s value. (58-60, 74, 88)... 

Lewis, F.W., Rector, W.G. Caffeine clearance in cirrhosis. The value of simplified determinations of liver metabolic capacity. J. Hepatol. 1992 14 157-162... 

Soucek and Vlachova 1960 Vesterberg and Astrand 1976). None of these studies provided evidence of saturation of trichloroethylene metabolism in humans. The data of Nomiyama and Nomiyama (1977) and of Ikeda (1977) indicated that the liver s capacity for metabolizing inhaled doses of trichloroethylene is... 

Hepatocellular damage manifests as elevated serum aminotransferases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)]. The degree of transaminase elevation does not correlate with the remaining functional metabolic capacity of the liver. An AST level two-fold higher than ALT is indicative of alcoholic liver damage. 

Elevations of serum transaminase concentrations generally are not correlated with the residual capacity of the liver to metabolize drugs, so these markers cannot be used directly as guides for residual metabolic capacity. Hepatically cleared TB drugs include isoniazid, rifampin, pyrazinamide, ethionamide, and p-aminosalicylic acid.39 Ciprofloxacin is about 50% cleared by... 

Overall, the human intestine is capable of metabolizing UDP-glucuronyltransferase substrates, although the rates of metabolism are between 5- and 10-fold lower than those observed in human liver microsomes. However, the presence of a metabolic capacity towards UDP-glucuronyltransferase substrates at the level of the enterocyte can exert a significant gut wall first-pass extraction on oral administration. 

The over-production of bilirubin to the point at which the liver s capacity to metabolize is exceeded or if there is dysfunction of the liver itself due to damage or metabolic immaturity, can lead to a yellow discolouration of tissues called jaundice. The accumulation of unconjugated bilirubin in neonates, often as a result of antibody-mediated destruction of the baby s red cells is dangerous as serious and irreversible brain damage can occur. Acute or chronic damage to the adult liver (hepatitis) may cause jaundice but not brain damage. 

The primary organ of biotransformation is the liver, although some other tissues have a degree of metabolic capacity, including the GI tract, kidneys, and even the skin. Depending on the route of administration. 

Proteins and other macromolecules are mainly cleared by high-capacity elimination processes such as renal hltration and liver metabolism. A coadministered drug can affect these processes and lead to serious drug-drug interactions. In addition, drugs that influence receptor-mediated clearance of the therapeutic protein may also result in important drug-drug interactions. 

The disposition of poorly extracted drugs, e.g. thiopentone (ER 0.16) and diazepam (ER 0.02), is more sensitive to changes in the metabolic capacity of the liver than to blood flow. 

The half-life will be independent of the dose, provided that the elimination is first order and therefore should remain constant. Changes in the half-life, therefore, may indicate alteration of elimination processes due to toxic effects because the half-life of a compound reflects the ability of the animal to metabolize and excrete that compound. When this ability is impaired, for example, by saturation of enzymic or active transport processes, or if the liver or kidneys are damaged, the half-life may be prolonged. For example, after overdoses of paracetamol, the plasma half-life increases severalfold as the liver damage reduces the metabolic capacity, and in some cases, kidney damage may reduce excretion (see chap. 7). 

Park BK. Assessment of the drug metabolism capacity of the liver. Br J Clin Pharmacol 1982 14 631. 

Although the bulk of published investigations of the induction of monooxygenase enzymes have dealt with the mammalian liver, induction has been observed in other mammalian tissues and in nonmammalian species, both vertebrate and invertebrate. Many induced CYPs have now been cloned and/or purified from a variety of species. It is clear that many of these induced CYPs represent only a small percentage of the total CYP in the uninduced animal. For this reason the constitutive isozymes, those already expressed in the uninduced animal, must be fully characterized because they represent the available xenobiotic-metabolizing capacity of the normal animal. 

The placenta is permeable to many types of drugs and chemical pollution. Especially lipophilic and nonionized substances with low molecular weight (< 500-1000) can pass rapidly. Not all fetal blood passes the liver. Furthermore, the liver develops its metabolizing capacity only gradually, which is far from complete at birth. Renal excretion of adverse chemicals is likewise very limited during most of the gestation period. Therefore a wide range of potentially harmful chemicals which easily reaches the fetus may hardly or not... 

Metabolic capacity changes across the life span. Hepatic metabolic capacity rises to a peak around 16 years of age and then declines. In the elderly, hepatic blood flow is reduced by up to 40%. This means that delivery of the drug to the liver is less, leading to reduced metabolism and a longer half-life. Elimination of drug and also drug metabolites is affected. Renal mass may decrease with age, as may... 

One of the more interesting and clinically relevant aspects of the drug-metabolizing capacity of the liver is that it is subject to fluctuations in activity. As mentioned previously, the basal rate of many liver enzymes can be modified by a number of factors... 

Organ slices are applicable to long-term cultures, viability up to 72 h has been described for rat liver slices (Fisher 1995). On the other and, investigation of enzyme activity revealed changes in the metabolic capacity of phase I and phase II enzymes in long-term cultures (Vandenbranden 1998). De Kanter (1995) established a general method for cryopreservation of slices. The best viability of rat liver slices was found by exposure for 30 minutes to 12 % dimethyl sulfoxide... 

Interaction studies in isolated/cultured hepatocytes and liver slices have to be assessed critically since a couple of competing reactions occur e.g. uptake pathways or phase II metabolism of the NCE and/or marker substrate, which makes it extremely difficult to interpret the data mechanistically. Additionally, metabolic capacity of hepatocytes in culture change with time (e.g. decrease/increase of phase I and phase II enzyme activities and internalization of transporters). Usually, Michaelis-Menten kinetics does not apply directly. For reliable results, interactions studies have to be performed in hepatocytes from at least three different donors since pooled hepatocytes are not available yet. Similar problems are also discussed for interaction studies in liver slices (Ekins 1998). 

The synthetic and metabolic capacity of this patient s liver is unlikely to be affected by the isolated rise in ALT and drug handling is unlikely to be altered. It is important to ensure that the patient has no signs of... 

---