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Topic 11.docx

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HLTH 340
Steve Mc Coll

Topic 11: Toxicokinetics - Excretion Definitions  What are some key definitions within this discussion? Expound as necessary. o Excretion: removal of an endobiotic or xenobiotic out of the body in waste matter  Mainly in urine and feces  Urine is a liquid material manufactured by the kidneys  Feces -- waste matter from digested food but ALSO the liver contributes to it (recall how bile is created in the liver and secreted into the intestine where all the food is)  May or may nor require energy (some passive, some active) o Secretion: transport of an endobiotic or xenobiotic out of body by a non-waste fluid  Requires energy (transporter or pump)  Often secondary route of xenobiotic elimination (e.g. breast milk, semen) -- more later o Elimination: removal of a xenobiotic from the bloodstream by a combination of biotransformation (metabolism) and excretion o Clearance: removal of a xenobiotic from bloodstream by a combination of tissue sequestration (distribution), biotransformation (metabolism) and excretion  It is more general to be aware of the difference Excretion Pathways  Discuss the major excretion pathways. o kidney: urinary excretion (mainly hydrophiles) o liver: biliary excretion (mainly lipophiles)  Discuss the secondary excretion pathways. o air: passive diffusion into exhaled air in lungs  mostly low MW volatile lipophilic compounds (organic solvents), because they can create a concentration gradient between the blood and the air, and this is how they get into the air and are breathed out o sweat, saliva, tears: they are sometimes useful for diagnostic purposes  Notably they are not of enough volume to be a major route of elimination o breast milk: it can be a significant route for elimination of toxins from the woman's body (recall how the lipophilic substances come out here)  However, it is better to do this into a breast pump rather than giving it to the baby -- for obvious reasons o semen: it is less major but still can be harmful for the woman if she is receiving the semen into her genital tract Kidney Nephron System  Give an overview of how the kidney's system works. o It is made up of hundreds of thousands of nephrons, which are the functional unit of the kidney  Essentially they each work as a filtration system for the blood -- so we pump blood through the nephrons and they take certain (wastes) things out of it o We start with the afferent arteriole, which delivers blood for the systemic circulation to the kidney o So blood is going through this arteriole but it turns into capillaries -- which are shaped like a ball, and we call it collectively the "glomerulus"  Notably these capillaries are very leaky, meaning that a lot of the constituents of the blood can pass through the capillary walls and into the surrounding tubular system, known as the Bowman's Capsule  In fact, 1/4 to 1/3 of everything comes into the tubule  Indeed the glomerulus is not selective -- so EVERYTHING comes out here -- even stuff that we want to keep such as Na, K, Cl, etc. (later we will see why this is OK) o Now let's follow the path of the filtrate (aka "ultrafiltrate") -- the stuff that leaves the capillary and goes into the Bowman's Capsule -- this filtrate continues through a tubule system: the loop of Henle, the proximal convoluted tubule, and the distal convoluted tubule  During this entire time, stuff is going from the tubules BACK INTO the arteries (i.e. the efferent arteriole) to rejoin the blood from which it came o However, not everything rejoins the blood -- the stuff that stays in the tubule system is what is eventually excreted as urine  Relate this process back to something we care about. o Well the point is that xenobiotics are amongst the things that move into the tubules from the glomerulus, and so we have to learn about whether they eventually go back into the blood (a bad thing) or stay in the tubules and are excreted as urine (a good thing) o Firstly we note that as more and more liquid gets moved back from the tubule into the blood stream, the XB's (and other stuff) become more concentrated and so a gradient is formed -- so we have a source of energy o Now the only thing left to consider is whether the xenobiotics can take advantage of the gradient  It turns out that tubule walls are not as permeable as the glomerulus was - - in fact there are TIGHT INTERCELLULAR JUNCTIONS  Consequence? Only lipophilic xenobiotics can get back across -- no dice for hydrophilic guys  NOTABLY, conjugated lipophilic materials can be excreted because their conjugated thing makes them hydrophilic Chelation of Metal Ions  Give an overview of what chelation is. o It is a way to speed up the excretion of certain materials by using a special material called chelation agent -- a simple and small molecule that binds tightly and selectively to certain metal ions  Chelate is "claw" -- when you look at molecular structure of a certain agent, they all have a structure where they can hold onto a metal ion in some sort of claw-like arrangement -- and they can do so quite tightly (although they are not irreversible -- more often it is "semi-reversible") o This does a few things:  Firstly, it will tie up the metal ion in such a way that it may not be bioavailable to enter certain body tissues -- so it affects distribution  Secondly, it will make the chelated metal more available for excretion -- the chelating agent could bind a heavy metal in a tissue, pull it out of the tissue to the bloodstream, then it will be more available to the kidney for excretion  The third thing it may do is protect the kidney in some cases (but not others) from the toxic effects of the heavy metal itself  Remember that the kidney is quite vulnerable to the toxic effects of certain heavy metals -- so if we are trying to clear something out of the bloodstream and into the urine, we have to be aware that the kidney itself could be damaged as a result  Discuss one chelator in particular, and how it can be both good and bad. o OK it is called dimercaprol, also known as BAL ("British anti-Lewisite")  Lewisite was a chemical warfare agent which exerted its effects via arsenic, and so BAL counteracted this by binding to arsenic in ways described previously o An examination of the diagram reveals that BAL has two thiol groups, meaning that they are nucleophilic and seek positive charges -- i.e. arsenic is a divalent cation, as are other substances which will be discussed shortly o So that said, BAL can do us good by binding to things such as:  Arsenic (as discussed)  Inorganic mercury: good against mercury poisoning  Lead (with EDTA): the idea here is that it will bind lead but not very tightly, which is BAD because when it performs the second function listed above, it can pull lead out of sinks in the body (i.e. bone) where it is doing no harm, and put it in the bloodstream where it IS harmful  Furthermore it can also make it even a little bit more lipophilic, rendering the kidney less able to excrete it  SOLUTION: administer BAL to get the lead out of the sinks, but provide EDTA (more later) in the bloodstream to take over from there o BAL can also bind to bad things:  Cadmium: as with lead, if it does this then brings it to the kidney, it can reall
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