Binding to tissue

The activity of factor Vila is enhanced astronomically (10 millionfold) upon binding to tissue factor. The VII or VHa-tissue factor complex activates factors IX and X and autoactivates factor VII. Although the activity of the tissue factor-factor VII complex is expressed without the presence of the negatively charged phosphatidylserine, the activity can be enhanced by its presence (9). 

The benzene ring per se does not impart any particular pharmacological response to a drug. It is widely held that its planarity, its ability to bind to tissue receptors by Van der Waals and charge transfer mechanisms, and, particularly, its ability to serve as a conductor of electrons within a substance serve as modulators, enhancing or diminishing the intensity of response to a molecule that is otherwise inherently bioactive. 

Covalent binding to tissue macrbmofecules Excreted via Lungs /... 

A study by Young et al. (1977) showed that retention and excretion of acrylonitrile are not directly proportional to dose. The data suggest a saturation process, perhaps due to covalent binding to tissue macromolecules. Seventy-two hours after administration of single oral doses of either 0.1 or 10 mg/kg, the proportion of the dose retained in the carcass was 37% at the low dose (0.1 mg/kg) and 27% at the high dose (10 mg/kg). 

IgE binds to tissue receptor sites through its F region, leaving the Fab region free to react with the allergen. The half-life of IgE is 2 days... 

Pentamidine is not well absorbed from the intestinal tract after oral administration and generally is given by intramuscular injection. The drug binds to tissues, particularly the kidney, and is slowly excreted, mostly as the unmodified drug. It does not enter the central nervous system (CNS). Its sequestration in tissues accounts for its prophylactic use in trypanosomiasis. 

Antimonials are irritating to the intestinal mucosa and therefore are administered by intramuscular or slow intravenous injection. Peak blood concentrations occur in 2 hours. These drugs bind to cells, including erythrocytes, and are found in high concentrations in the liver and spleen. As compared with the trivalent antimonials, which are no longer used, the pentavalent antimonials bind to tissue less strongly. This results in higher blood levels, more rapid excretion, and lowered toxicity. Pentavalent antimonials are rapidly excreted in the urine, with up to one-half of the administered dose excreted in 24 hours. 

Pyrimethamine is well absorbed after oral administration, with peak plasma levels occurring within 3 to 7 hours. An initial loading dose to saturate nonspecific binding sites is not required, as it is with chloroquine. However, the drug binds to tissues, and therefore, its rate of renal excretion is slow. Pyrimethamine has a half-life of about 4 days. Although the drug does undergo some metabolic alterations, the metabolites formed have not been totally identified. 

Like other aromatic amines 4-chloro-ort/20-toluidine has been shown to undergo metabolic activation resulting in covalent binding to tissue proteins, DNA and RNA both in vivo and in vitro (Hill et al., 1979 Bentley et al., 1986a,b Bimer Neumann, 1988). 

Ahmed et al. (1982) examined the distribution of [l- Cjacrylonitrile (46.5 mg/kg bw orally) in rats. Some 55% of the dose was recovered in the excreta in 24 h (urine, 40% faeces, 2% exhaled as CO . 9% as H (. 0.5% and acrylonitrile, 4.8%). In addition to appreciable retention in the erythrocytes (a feature of the behaviour of meta-bolically formed thiocyanate noted by Bollard et al., 1997), there occurred covalent binding to tissue macromolecules in liver, kidney, spleen, brain, limg and heart. Ahmed et al. (1983) also compared the tissue distribution of [l- C]- and 2,3- - C]aciylonitrile in rats at the same dose level (46.5 mg/kg bw). There was much more covalent binding of radioactive species in all organs examined after administration of [2,3- - C]acr lo-nitrile, suggesting that metabolites other than thiocyanate play a major role in its retention in the body. 

Cote et al. (1984) and Vodicka et al. (1990) observed marked decreases in glutathione levels in a variety of organs such as brain, lung, liver and kidney of rats dosed with acrylonitrile either subcutaneously (75 mg/kg bw) or by inhalation (75-300 mg/m3). These effects were less pronounced in mouse and hamster tissues. Covalent binding to tissue protein, a dose-dependent decrease in tissue glutathione, and an... 

Natural IFN-p is predominantly synthesized by fibroblasts. Its sequence is 30% homologous to that of IFN-a. The receptors for both IFN-a and -p are the same but the fit of the receptor is different for the two agonists. There are also differences between IFN-a and -p in structure (IFN-p is glycosylated on one site, pharmacokinetics and binding to tissues. 

Treatment of animals with A-acetylcysteine, a precursor of glutathione, protects animals against acetaminophen-induced hepatic necrosis, possibly by reducing covalent binding to tissue macromolecules. However, depletion of glutathione potentiates covalent binding and hepatotoxicity. 

In animal studies of nephrotoxicity not only can histopathology be carried out but various biochemical parameters can be compared with those from untreated animals. They include lipid peroxidation and covalent binding to tissue macromolecules. 

Factor VII exhibits a weak procoagulant activity on its own, typically accounting for about I -2% of the total factor Vll/Vlla activity (17), Upon binding to tissue factor, a 10,000,000-fold increase in factor Vila enzymatic activity is observed (18). Both factor VII and factor Vila bind to tissue factor with equal affinity (19), How factor VII is initially activated is not known, though it is hypothesized that factor Xa can activate factor VII in a back-activation reaction. The factor VIla—tissue factor complex can then activate factor X leading to the generation of thrombin and ultimately to the formation of fibrin strands. 

---