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Topic 7.docx

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University of Waterloo
HLTH 340
Steve Mc Coll

Topic 7: Toxicokinetics - Distribution Part 2 Distribution - sequestration mechanisms  What is sequestration? What are the major varying factors? o It is when a xenobiotic is confined in a specific tissue in body  Notably, the tissue is usually not seriously affect by the sequestered xenobiotic (although there are exceptions) o It can vary in different ways:  Whether it is reversible  How long something remains sequestered for before leaving  What does sequestration do for bioavailability? o It REDUCES it in the blood stream (because an XB is now in the tissues and not in the blood!) o Also, it (indirectly) reduces XB concentration in the target tissues of the XB, because you need to be in the bloodstream in order to get to your target tissue!  What (good) consequences does this have on drug toxicity/overdose? o Well when a XB is sequestered, it may not be immediately available to exert toxic effects or pharmacologic effects on active body tissues -- and so it may provide partial protection from acute toxicity or drug overdose  In terms of a dose-response curve, it "smoothes out" the peak because the concentration does not spike quite as sharply o The thing is, especially when sequestration is reversible, we have to realize that it DOESN'T BLOCK a drug completely -- it just slows down its effect  What (bad) consequences does this have on drug toxicity/overdose? Include a discussion of body burden. o Well the bad thing is that when an XB is sequestered, it PERSISTS for a longer time in the body -- because it is not available to get broken down and/or excreted (i.e. biotransformation)  This is how "body burden" frequently develops -- recall that body burden is the total amount of some substance in our body  REALIZE THAT body burden is not necessarily harmful because:  It's just the amount of some substance (not necessarily toxic)  And also, a high body burden even of something bad is not automatically harmful unless all that sequestered stuff gets mobilized o In terms of practical effects, it means that DRUG ACTION is prolonged and the toxic effects of POLLUTANTS can be prolonged  For example, recall the discussion (more later) of how lead that we are exposed to when we are young can screw us over later in life Target tissue  What is a target tissue with respect to a given XB? Even if we have a XB-target tissue match, what can prevent the effect from being seen? o The deal is that for each XB, it will usually only exert effects on very specific tissues because they need particular receptors on the tissue (for example) in order to make a difference  In fact, very few drugs/chemicals are effective in all tissues o Even if we have that match, a toxic effect is possible only when a xenobiotic is bioavailable to distribute from blood to target tissue  What this means is that the xenobiotic still has to be able to GET TO the target tissue, and as we will discuss later this can be affected by things like:  Whether the thing is sequestered somewhere before it can get to the tissue  Whether there is a barrier (think the BBB or BTB) blocking the target tissue  (more factors given in the next point)  What are some of the factors that affect blood flow (and thus ultimately XB access to) target tissues? o tissue perfusion rate by arterial blood supply o plasma protein binding or RBC binding in blood o tissue/blood partition coefficient Kp(tissue/blood) o internal membrane barriers (e.g. BBB) o sequestration in non-target issues  Explain the concept of the tissue/blood partition coefficient further. o OK, remember how within the blood there is a Ko/w coefficient which tells us how much something will tend to bind to proteins (if it is lipophilic and Ko/w > 1) or just be free in the watery blood (if it is hydrophilic and Ko/w < 1)? We have here an analogous concept (also based on lipophilicity) where a substance is also in a partition between the TISSUE and the BLOOD  This is because (sometimes) the tissue can be lipophilic (i.e. fatty tissue) so a given XB will either tend to accumulate in the tissue or in the blood (which is more hydrophilic) o However, of COURSE the nature of the tissue will affect this relationship -- because sometimes the tissue will be hydrophilic or other times it will be more lipophilic  Hydrophilic tissues (such as muscle, which is "watery") will have a Kt/b of 1:1, because it is just as hydrophilic as the blood is  However, for lipophilic tissues (such as adipose tissue or even the brain) would have a Kt/b of 100:1 or 1000:1, which is pretty crazy  Of COURSE we should note that the Kt/b also depends on the substance itself -- whether it is hydro or lip  i.e. We might find that with DDT, there is way more stored in a fatty cell than vs. the bloodstream because DDT is lipophilic 3 Types of Sequestration Processes  Discuss the 3 types of sequestration processes. For each, be sure to include the typical body tissues involved, the nature of the relationship, and the extent of reversibility. o Pool  OK, so there is a "fast exchange" here which means that the equilibrium between blood and tissue is freely reversible and also, flipping back and forth is very FAST  So the nature of the relationship is an equilibrium between plasma and ACTIVE tissues/cells The body tissues involved include:   Intracellular fluid (i.e. cytosol, which is mostly water and thus hydrophilic)  Synovial fluid (fluid found in the cavities of synovial joints, i.e. your shoulder) o Depot  Here there is a "slow exchange", which means that stuff can go back and forth between tissue and blood, but not very fast  The nature of the relationship is more of a STORAGE thing than an equilibrium  The body tissues involved are structural components and tissue reservoirs:  Adipose tissue (fat)  Connective tissue  Bone o Sink  Here we are talking about irreversibility, which means that the XB doesn't really go back and forth at all (although as we will discuss later, there ARE ways to "mobilize" XB's from a sink)  The nature of the relationship is thus one of PERMANENT COVALENT BINDING  The body tissues involved include:  Adipose tissue (again)  Bone  Skin a
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