Tissue Level Transport

According to the Federal Research in Progress Database, Perry and Tsao at the Lawrence Berkeley Laboratory are studying the chemical species and transport of thorium in soil. In other on-going projects, Krey et al. at Environmental Measurements Laboratory in New York are studying the daily intake of thorium, and Mclnroy et al. at Los Alamos National Laboratory are studying the tissue levels of thorium in the general population and occupationally exposed individuals. 

Depletion of ATP is caused by many toxic compounds, and this will result in a variety of biochemical changes. Although there are many ways for toxic compounds to cause a depletion of ATP in the cell, interference with mitochondrial oxidative phosphorylation is perhaps the most common. Thus, compounds, such as 2,4-dinitrophenol, which uncouple the production of ATP from the electron transport chain, will cause such an effect, but will also cause inhibition of electron transport or depletion of NADH. Excessive use of ATP or sequestration are other mechanisms, the latter being more fully described in relation to ethionine toxicity in chapter 7. Also, DNA damage, which causes the activation of poly(ADP-ribose) polymerase (PARP), may lead to ATP depletion (see below). A lack of ATP in the cell means that active transport into, out of, and within the cell is compromised or halted, with the result that the concentration of ions such as Na+, K+, and Ca2+ in particular compartments will change. Also, various synthetic biochemical processes such as protein synthesis, gluconeogenesis, and lipid synthesis will tend to be decreased. At the tissue level, this may mean that hepatocytes do not produce bile efficiently and proximal tubules do not actively reabsorb essential amino acids and glucose. 

GSH is not transported into cells. For circulating GSH to increase intracellular GSH concentrations, it must first be hydrolyzed to Glu and CysGly, which are subsequently transported into the cell and serve as substrates for GSH synthesis. Thus, GSH administered orally or parenterally, and that produced by the liver and released into the circulation enhance tissue levels of GSH by providing a source of its constituent amino acids. In contrast, GSH monoesters, which are well absorbed after oral administration, as is GSH, are readily transported to cells and then hydrolyzed to GSH and the corresponding alcohol. Thus, higher cellular levels of GSH result from oral administration of GSH monoesters than from oral administration of comparable doses of GSH. 

Similar equations can be written for all relevant compartments. If parameters are chosen, the resulting set of nonlinear ordinary differential equations can be solved numerically to yield predictions of the concentration of the drug and metabolite(s) in each of the compartments as a function of time. Of course, the simplifying assumptions here can be relaxed to include much more detail concerning plasma and tissue binding, transport at the level of the blood capillary and cell membrane, and spatial nonuniformity — but at the cost of increasing complexity and the requirement for more parameters. 

In muscle and adipose tissue, insulin promotes transport of glucose and other monosaccharides across cell membranes it al.so facilitates tran.sport of amino icids, potassium ion.s. nucleosides, and ionic phosphate. Insulin also activates certain enzymes—kinases and glycogen. synthetase in muscle und adipose tissue. In adipose tissue, insulin decreases the release of fatty acids induced by epinephrine or glucagon. cAMP promotes fatty acid release from adipose ti.ssue therefore. it is pos.sible that insulin decreases fatty acid release by reducing tissue levels of cAMP. Insulin also facilitates the incorporation of intracellular amino acids into protein. 

Figure 10.15 Graphical representation of the terminal distribution stage when plasma concentrations drop below tissue levels and the net transport of drug is from tissue to plasma.

Pharmacokinetics describes the time dependence of transport and distribution of a drug in the different compartments of a biological system, e.g. by rate constants of absorption, blood and tissue levels, and metabolism and elimination rate constants. Quantitative structure-pharmacokinetics relationships [433, 442, 451, 452, 472, 761 — 766] investigate the structural dependence of such parameters within groups of chemically related compounds. 

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