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Topic 3.docx

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HLTH 340
Steve Mc Coll

Topic 3: Toxicokinetics - General Principles and Absorption Part 1 Toxicokinetics - General Principles Pathways  So if we were to think about a xenobiotic entering the body, what is the "life cycle" of toxicokinetic processes which we would see occuring? Name and discuss each. o Absorption: the entrance of the xenobiotic from the external environment into our body (specifically, bloodstream)  In order for absorption to happen, the XB must get past (usually) 1 of 3 external membrane barriers: the skin, the GI tract, and the lungs  Once the xenobiotic has penetrated, it is then in the bloodstream -- or blood plasma (cell-free portion of the blood) o Distribution: once the xenobiotic is in the bloodstream, it can travel anywhere in the body  The 3 main "types" of locations where it can end up are pools, depots, and sinks  Sinks are locations where the xenobiotic will NOT leave from once it has reached there -- thus we say that the transport of a xenobiotic into a "sink" is irreversible, and the XB is "sequestered"  i.e. lead can go to bones/teeth and stay there  However, pools and depots are reversible -- the xenobiotic can go there, settle for a time, then re-enter the bloodstream and be distributed somewhere else o Metabolism: here we are trying to change the structure of the XB through chemical reactions, so as to use/eliminate it  This happens in 2 stages:  Degradation: breaking down the XB  Conjguation: attaching something to the XB (perhaps to neutralize it)  There are a few qualifications to make:  Notably, metabolism is not always successful in breaking down the XB and readying it for excretion  Also, metabolic processes have the POTENTIAL to make something more (not less) toxic o Excretion: here we excrete the xenobiotic through different routes  The routes include body parts: kidney, liver, lungs  And also actual excretions: saliva, sweat, breast milk  Talk about the relationship that is present between all of these substances. o We need to realize that these processes don't occur in sequence -- i.e. not always absorption then excretion etc. o In fact, a lot of times, PHARMACEUTICALS do them all at once (missed the reason why)  Now discuss another pathway -- this time in more general terms than the first one. o Alright, this pathway involves both toxicokinetics (recall, it is the entrance and processing of XB's) and toxicodynamics (what the XB does to the body) o The pathway is as follows:  External dose/exposure  Toxicokinetic pathways:  Internal/dose exposure  Remember that for many different reasons, the internal dose is not the same as the external dose  Tissue dose/exposure  And then even once it gets into the body, some tissues may be affected more (esp. the ones involved or near the absorption) than others  Cellular/subcellular dose  Toxicodynamic pathways:  Cellular/subcellular interaction  Obviously the interaction will be different depending on the particular XB  Early physiological response  This is (possibly) analogous to the notion of an ACUTE reaction  Late response  This is (possibly) analogous to the notion of an CHRONIC reaction -- the idea that the response won't manifest right away; it will take some time to build up  Irreversible pathology Absorption Part 1 Absorption in More Detail  OK, now let's think about all the different barriers than an XB would have to cross in order to get into a cell (where the toxicodynamics start, see above). For each barrier, explain where the XB would be coming from, as well as any other notes. o Mucosa/skin: the XB would pass through here from the external environment  Here the success of absorption is affected by things like:  Sebaceous glands on the skin that make it acidic and thus easier/harder for an XB to survive and penetrate  Other substances in the intestine that affect the environment and in turn the ability of an XB to survive in the intestine and come through the gut mucosa o Capillary membrane: the XB can enter from "outside" (interstitial fluid) or exit from "inside" (blood plasma)  The ability of the XB to get in and out of here allows it to take advantage of the bloodstream to go wherever it needs to go within the body o Tissue cell membrane: the XB would enter here from the interstitial fluid Once it gets into the cell, it can start doing cool stuff  o Organelle membrane: the XB would enter here from the intra-organelle fluid -- i.e. the cytoplasm  Reproduce the figure on Slide 4 (Lecture A2.ppt).  OK, now let's talk in more detail about the absorption section of that diagram. Where do things go after they have been absorbed? What are the 3 major routes of "natural" exposure to something? What are some artificial routes? Explain. o As said before many times, XB's go to the blood or LYMPHATIC FLUID after they have been absorbed o There are 3 major routes of "natural" (accidental?) exposure to an XB:  Oral: we ingest something -- and it eventually enters our system through the gut  Respiratory: we inhale something and it goes through the alveoli into our system  Dermal: percutaneous -- through UNBROKEN skin o
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