DISTRIBUTION STORAGE AND EXCRETION BISC 312 Simon Fraser

DISTRIBUTION, STORAGE AND EXCRETION BISC 312 Simon Fraser University 2004 Onkar Bains

Toxicokinetics Absorption n Distribution n Metabolism n Storage n Elimination n

What happens after absorption? n Bind to something immediately n n Proteins DNA n Go directly to the liver and get detoxified n Get transported to other parts of body

DISTRIBUTION

Distribution n Process whereby an absorbed toxicant moves away from the site of absorption to other areas of the body n Questions to think about: n n n How do chemicals move through the body? Does distribution vary with the route of exposure? Is a chemical distributed evenly to all organs or tissues? How fast is a chemical distributed? Why do some chemicals stay in the body for a long time whereas others are eliminated quickly?

Distribution n Once absorbed, xenobiotic enters: n ________ system n n n Heart, arterial vessels, venous vessels, capillaries Medium of transport = _______________ system Lymph capillaries, lymph nodes, lymphoid tissue (spleen, thymus, etc) n Medium of transport = ______ n

Routes for Toxicants to Take n After absorption by GI tract: n Carried by blood to _____ by portal system n Thus, xenobiotics entering from the GI tract are immediately subject to biotransformation or excretion by the liver—“______________" n Blood from liver flows to heart and then to lungs, before going to other organs n First pass effect also for _________ injection

Routes for Toxicants to Take n Xenobiotic that enters _______ of intestinal tract will not go to liver first but will slowly enter systemic circulation n Proportion of xenobiotic moving by lymph is much smaller than that transported by blood

Routes for Toxicants to Take n After absorption via lungs or skin: n Enters blood and goes directly to heart and systemic circulation n Xenobiotics are thus distributed to various organs of body before it goes to liver = not subject to _________ n Same is true for _________ injected drugs/xenobiotics

Factors affecting distribution n Properties of Toxicant n Concentration Gradient n Blood Flow n Tissue Affinity n Structural barriers to Toxicant Entrance

Properties of Toxicant n _______ and _______ are again of concern n Smaller, non-polar toxicants gain preferential entrance

Concentration Gradient n Referring to amount of xenobiotic in blood as compared to tissues n Following absorption, toxicant will be diluted by fluid volume present in organism n Fluid volume found in three separate sites: n n n _________________

Concentration Gradient n Dilution and xenobiotic concentration at any of fluid sites are important, since passive transport of toxicant into/out of these sites will be determined by toxicant’s concentration gradient

Blood Flow n Two parameters affect accumulation of xenobiotic in an organ: n Volume of blood flowing through organ n ______ of organ

Blood Flow n Combination of these two factors (blood flow/mass ratio) permits comparison of toxicant accumulations in different organs n High blood flow/mass ratios = ___________ n Intermediate blood flow/mass ratios = _________ and _____ n Low blood flow/mass ratios = ______ and ________

Tissue Affinity n Some tissues have higher affinity for specific chemicals and will accumulate a xenobiotic in great concentrations in spite of a rather low flow of blood n For example, adipose tissue concentrates lipid-soluble toxicants n Once deposited in these storage tissues, xenobiotics may remain for long periods of time, due to their solubility in tissue and relatively low blood flow

Structural Barriers n During distribution, passage of toxicants from capillaries into various tissues or organs is not uniform n Structural barriers exist that restrict entrance of toxicants into certain organs or tissues n Primary barriers are those of the _________, and _____

Structural Barriers n Blood Brain Barrier n Placental Barrier n Casparian Strip

Blood Brain Barrier n Not totally _______, but slows down rate at which xenobiotics cross into brain tissue while allowing essential nutrients, including oxygen, to pass through n What makes this barrier? n n n tightly joined ________—barrier to small to medium water soluble molecules _________ that move chemicals back into blood _________ add protection–barrier to small to medium water soluble molecules

Astrocytes From http: //www. kumc. edu/instruction/medicine/anatomy/histoweb/nervous/nerve 15. htm

Blood Brain Barrier n _______ enhances penetration n _______ diminishes penetration n Carrier mediated transport of xenobiotics n n _________ combines with cysteine (forms a complex that resembles methionine) and is accepted by large neutral amino acid carriers BBB not fully developed at ______ and makes ____ more susceptible

Placental Barrier n Protects developing fetus from most xenobiotics distributed in the maternal circulation n Consists of several cell layers between maternal and fetal circulatory vessels in placenta n Lipids in cell membranes limit the diffusion of water-soluble xenobiotics n However, nutrients, gases, and wastes of developing fetus can pass through placental barrier

Placental Barrier n Not totally impenetrable but effectively slows down the diffusion of most toxicants from mother into fetus n _________________________

n Casparian Strip Barrier in ______ n Located in _____ n Composed of _______ and _____ n Surround vascular tissue i. e. xylem and phloem n Impermeable to water and ions (metals)

Other Distribution Mediums n Besides blood and lymph, other distribution mediums are: n ______________________ n ___________

STORAGE

Storage n Binding or dissolving into body tissues alters distribution n Stored xenobiotics are in equilibrium with blood n As xenobiotic is metabolized or excreted more toxicant is released from storage site

Storage n Permanent n n Temporary n n Mercury in the hair DDT removed from the fat tissues and excreted Toxicants are stored for varying lengths of time

Storage Sites Blood proteins n Liver and kidney n Fat n Bone n Nucleic Acids n Hair n Cell wall and vacuoles n

Storage Sites: Blood proteins n _________ n n n 60 -80% of plasma proteins most important in maintenance of osmotic balance produced by liver From http: //www. biology. eku. edu/RITCHISO/301 notes 4. htm n _________

Storage Sites: Blood proteins n _________ n n n alpha & beta n some are important for transport of materials through the blood (e. g. , thyroid hormone & iron) n some are clotting factors n produced by liver gamma globulins are immunoglobulins (antibodies) produced by lymphocytes _________ n n important in clotting produced by liver

Storage Sites: Blood proteins n _______ is most abundant circulating plasma protein AND most common plasma protein to which xenobiotics are bound n Xenobiotics bound to plasma proteins are STORED, even though toxicant-plasma protein complex continues to circulate

Storage Sites: Blood proteins n Binding to proteins _______ exposure and availability (may be temporary) n Binding may be detrimental n Example: _____ binding to hemoglobin

Storage Sites: Fatty tissues n _______-soluble xenobiotics are often stored in adipose tissues n Adipose tissue is located in several areas of body: n n Additional fat around kidneys __________________ In folds on surfaces of _____ and ______ From http: //www. udel. edu/Biology/Wags/histopage/empage/eat. htm

Storage Sites: Fatty tissues n ______ removal from these tissues n _____ blood supply n Eventually, xenobiotic may be ______ into blood for further distribution and elimination, or redeposited in other adipose tissue cells n Remobilization occurs during: n n n _______________

Storage Sites: Bone n Contains ______ blood supply but is a live organ n Composed of proteins and mineral salt __________ (Ca 10(PO 4)6(OH)2)— mammals

Storage Sites: Bone n Several chemicals, primarily elements, follow same kinetics as calcium and hydroxyl ions and therefore can be substituted for them in bone matrix n _________, _______ and _____ may be substituted for calcium n ______ may be substituted for hydroxyl ions

Storage Sites: Bone n Bone is continually being remodeled under normal conditions n Calcium and other minerals are continually being resorbed and replaced, on the average about every 10 years n Thus, any toxicants stored in matrix will eventually be released to re-enter circulatory system

Does storage make it safer? n Not absolutely: n ________ the concentration that reaches the target site…. BUT…. n Sometimes the storage site is the _____ site n ________ may occur

EXCRETION

Excretion n a. k. a. ______ or _______ n To excrete a toxicant it must ultimately cross or interact with a biological membrane

Excretion n Xenobiotics may be excreted in their original form or as a metabolite n Depends on the chemical properties of the xenobiotics n _______ xenobiotics may be excreted in their original form in urine n _______ xenobiotics require biotransformation before they can be excreted

Excretion Urinary excretion via kidney n Biliary excretion (bile) n Respiratory structures—exhaled air n Skin/sweat n Breast milk n Hair, saliva, tears n Abscission of leaves n

Urinary Excretion n Elimination of substances by kidneys into urine is _______ route of excretion of toxicants n Primary function of kidney is excretion of body wastes and harmful chemicals n Functional unit of kidney responsible for excretion is the _______

Urinary Excretion n Each kidney contains about _______ nephrons n Nephron has three primary regions that function in the renal excretion process n n n ________________

Urinary Excretion n Three processes are involved in urinary excretion: _____, ______, and ______

Urinary Excretion n Ultimate elimination of xenobiotic by kidney is greatly affected by: n n n _____ properties (primarily molecular size) _____ in urinary filtrate binding to _________ n Xenobiotics (both polar and lipid-soluble) are filtered with ease by glomerulus (< molecular weight of 60, 000 daltons) n Those substances that are _____ remain in the urine and leave body

Urinary Excretion n _______ xenobiotics can be reabsorbed and re-enter blood circulation, which lengthens their halflife in body and potential for toxicity n _____ substances usually do not bind with blood proteins and thus can be filtered out of the blood into tubule filtrate n In contrast, substances extensively bound to plasma proteins remain in blood—primarily the lipophilic xenobiotics

Urinary Excretion n Kidneys, which have been damaged by xenobiotics, infectious diseases, or as a consequence of age, have diminished ability to eliminate xenobiotics thus making those individuals more susceptible n Presence of _______ in urine indicates glomerulus filtering system is damaged letting large molecules pass through n Presence of _______ in urine is indication that tubular reabsorption has been impaired

Biliary Excretion n Compounds, including xenobiotics, divided into 3 classes on basis of their [bile]/[plasma]: n Class A n n Class B n n n Ratio =______ (i. e. Na, K, glucose, Hg, Co) Ratio ______ (i. e. bile acids, bilirubin, Pb, As, Mn) Ratio usually found between 10 to 1000 Class C n Ratio ______ (i. e. albumin, Zn, Fe, chromium)

Biliary Excretion n Compounds rapidly excreted in bile most likely from _______ n However compound does not have to be highly concentrated in bile for biliary excretion to be of quantitative importance n i. e. Hg—bile still main route of excretion for this slowly eliminated xenobiotic

Biliary Excretion n Class B uses ____ transporters n Class A/C transport = unknown n Liver has at least 4 active transport systems for excretion or organics into bile: n n ________ (2) _______________ (1) Liver also has 1 active transport system for inorganics (i. e. metals)

Biliary Excretion n However, _______ enzymes can hydrolyze some glucuronide and sulfate conjugates, which can release the less polar compounds that may then be _______ n Process of excretion into intestinal tract via bile and reabsorption and return to liver by portal circulation = ___________ From http: //www. sis. nlm. nih. gov/Tox. Tutor/Tox 2/a 53. htm

Biliary Excretion n Continuous enterohepatic recycling can occur and lead to very ______ half-lives (greater longevity) of some substances n For this reason, drugs may be given orally to bind substances excreted in bile n For example, a _____ is administered orally which binds with dimethylmercury (which had been secreted in the bile), preventing reabsorption and toxicity

Exhaled Air n Lungs represent an important route of excretion for xenobiotics (and metabolites) that exist in a gaseous phase in blood n Blood gases are excreted by ______ diffusion from blood into alveolus, following a concentration gradient n Gases with ____ solubility in blood are more rapidly eliminated than those gases with ____ solubility n ______ liquids dissolved in blood are also readily excreted via expired air

Exhaled Air n Exhalation is an exception to most other routes of excretion in that it can be a very efficient route of excretion for _____ soluble toxicants n WHY? . . . Due to very close proximity of capillary and alveolar membranes, which are thin and allow for the normal gaseous exchange

Skin and Sweat n ______ importance n Skin n Molting/Shedding Lipophilic compounds removed Sweat n n Under conditions of great sweat production, excretion in sweat may reach a significant degree Some metals, including Cd, Cu, Fe, Pb, Ni and Zn may be eliminated in sweat to some extent

Saliva n ______ importance n Xenobiotics that passively diffuse into saliva may be swallowed and absorbed by GI tract

Breast milk n Milk: n Since milk contains ______% lipids, lipid soluble xenobiotics can diffuse along with fats from plasma into the mammary gland n Substances chemically similar to calcium can also be excreted into milk along with calcium n Examples: ____, _________ and _______

Hair n Quantitatively _______ n Very low levels of excretion n _______ n Storage site until hair _____ or is ______

Excretory Organs/Systems used by other organisms n ____ in fish n _______ tubules in insects n ______ in crustaceans n ______________

Excretion: Abscission of leaves n In botany, the controlled separation of part of a plant from main plant body n Most commonly, the falling of leaves or the dropping of fruit controlled by _______ n Leaves left to rot on the ground n Possible ________?

Toxicokinetics: Summary n A toxicant must be absorbed into the body and distributed to target tissues before it can exert a toxic effect n How much is absorbed and where it’s distributed to in body depends on the physical/chemical properties

Toxicokinetics: Summary n Metabolism may be necessary before the toxicant is excreted n Therefore a toxicant may be: n n _____________________ Most favorable scenario for an organism: n A toxicant is absorbed, detoxified by metabolic processes, and excreted with no harm resulting