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  1. 1.
  2. 2. DISPOSITION OF CHEMICALS The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology , 5th ed., New York: McGraw-Hill, 1996).
  3. 3. Plasma Concentration Time Plasma concentration vs. time profile of a single dose of a chemical ingested orally
  4. 4.
  6. 6. Transfer of Chemicals across Membranes <ul><li>Passive transport determined by: </li></ul><ul><li>- Permeability of surface </li></ul><ul><li>- Concentration gradient </li></ul><ul><li>- Surface area </li></ul><ul><li>Permeability depends on: </li></ul><ul><li>For cell membranes: </li></ul><ul><li>- Lipid solubility </li></ul><ul><li>- pH of medium </li></ul><ul><li>- pK of chemical </li></ul><ul><li>For endothelium </li></ul><ul><li>size, shape and charge of chemical </li></ul>PASSAGE ACROSS MEMBRANES Passive Facilitated Active
  7. 7.
  8. 8. Factors Affecting Absorption (G.I., lungs, skin) <ul><li>Determinants of Passive Transfer (lipid solubility, pH, pK, area, concentration gradient). </li></ul><ul><li>Blood flow to site. </li></ul><ul><li>Dissolution in the acqueous medium surrounding the absorbing surface. </li></ul>
  9. 9. Factors Affecting Absorption from the GI Tract <ul><li>Disintegration of dosage form and dissolution of particles </li></ul><ul><li>Chemical stability of chemical in gastric and intestinal juices and enzymes </li></ul><ul><li>Motility and mixing in GI tract </li></ul><ul><li>Presence and type of food </li></ul><ul><li>Rate of gastric emptying </li></ul><ul><li>Intestinal vs. gastric absorption </li></ul><ul><li>FIRST PASS EFFECT </li></ul>
  10. 10. Absorption from the Lungs <ul><li>For gases, vapors and volatile liquids, aerosols and particles </li></ul><ul><li>In general: large surface area, thin barrier, high blood flow rapid absorption </li></ul><ul><li>Blood:air partition coefficient – </li></ul><ul><li>influence of respiratory rate and blood flow </li></ul><ul><li>Blood:tissue partition coefficient </li></ul>
  11. 11. Absorption of Aerosols and Particles : 1- Particle Size 2- Water solubility of the chemical present in the aerosol or particle REMOVAL OF PARTICLES Physical Phagocytosis Lymph Absorption from the Lungs
  12. 12. NasopharyngealRegion 5-30 µm Trachea Bronchi Bronchioles 1-5 µm Alveolar Region 1 µm DEPOSITION OF PARTICLES IN THE RESPIRATORY SYSTEM
  13. 13. Absorption from the Skin <ul><li>Must cross several cell layers (stratum corneum, epidermis, dermis) to reach blood vessels. </li></ul><ul><li>Factors important here are: </li></ul><ul><li>lipid solubility </li></ul><ul><li>hydration of skin </li></ul><ul><li>site (e.g. sole of feet vs. scrotum) </li></ul>
  14. 14. Other Routes of Exposure <ul><li>Intraperitoneal </li></ul><ul><li>large surface area, vascularized, first pass effect. </li></ul><ul><li>Intramuscular, subcutaneous, intradermal: absorption through endothelial pores into the circulation; blood flow is most important + other factors </li></ul><ul><li>Intravenous </li></ul>
  15. 15. Bioavailability Definition: the fraction of the administered dose reaching the systemic circulation for i.v.: 100% for non i.v.: ranges from 0 to 100% e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism First Pass Effect
  16. 16. Bioavailability Dose Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver to systemic circulation
  17. 17. Plasma concentration Time (hours) i.v. route oral route Bioavailability (AUC) o (AUC) iv
  18. 18. Principle For chemicals taken by routes other than the i.v. route, the extent of absorption and the bioavailability must be understood in order to determine whether a certain exposure dose will induce toxic effects or not. It will also explain why the same dose may cause toxicity by one route but not the other .
  19. 19. <ul><li>Plasma 3.5 liters . ( heparin, plasma expanders) </li></ul><ul><li>Extracellular fluid 14 liters. </li></ul><ul><li>(tubocurarine, charged polar compounds) </li></ul><ul><li>Total body water 40 liters. (ethanol) </li></ul><ul><li>Transcellular small. CSF, eye, fetus (must pass tight junctions) </li></ul>Distribution into body compartments
  20. 20. Distribution <ul><li>Rapid process relative to absorption and elimination </li></ul><ul><li>Extent depends on - blood flow - size, M.W. of molecule - lipid solubility and ionization - plasma protein binding - tissue binding </li></ul>
  21. 21. Distribution <ul><li>Initial and later phases: </li></ul><ul><li>initial determined by blood flow </li></ul><ul><li>later determined by tissue affinity </li></ul><ul><li>Examples of tissues that store chemicals: </li></ul><ul><li>fat for highly lipid soluble compounds </li></ul><ul><li>bone for lead </li></ul>
  22. 22. Distribution <ul><li>Blood Brain Barrier – characteristics: </li></ul><ul><li>1. No pores in endothelial membrane </li></ul><ul><li>2. Transporter in endothelial cells </li></ul><ul><li>3. Glial cells surround endothelial cells </li></ul><ul><li>4. Less protein concentration in interstitial fluid </li></ul><ul><li>Passage across Placenta </li></ul>
  23. 23. 100-fold increase in free pharmacologically active concentration at site of action. NON-TOXIC TOXIC Alter plasma binding of chemicals 1000 molecules % bound molecules free 99.9 90.0 100 1
  24. 24. Chemicals appear to distribute in the body as if it were a single compartment. The magnitude of the chemical’s distribution is given by the apparent volume of distribution (Vd). Amount of drug in body Concentration in Plasma Vd = PRINCIPLE
  25. 25. Volume of Distribution Volume into which a drug appears to distribute with a concentration equal to its plasma concentration
  26. 26.
  27. 27. Examples of apparent Vd’s for some drugs Drug L/Kg L/70 kg Sulfisoxazole 0.16 11.2 Phenytoin 0.63 44.1 Phenobarbital 0.55 38.5 Diazepam 2.4 168 Digoxin 7 490
  28. 28.
  29. 29. Elimination by the Kidney <ul><li>Excretion - major 1) glomerular filtration </li></ul><ul><li>glomerular structure, size constraints, protein binding </li></ul><ul><li>2) tubular reabsorption/secretion </li></ul><ul><li>- acidification/alkalinization, </li></ul><ul><li>- active transport, competitive/saturable, organic acids/bases -protein binding </li></ul><ul><li>Metabolism - minor </li></ul>
  30. 30. Nephron Structure The structure of the nephron (from A.C. Guyton, Textbook of Medical Physiology , Philadelphia, W.B. Saunders Co.; 1991
  31. 31. Elimination by the Liver <ul><li>Metabolism - major </li></ul><ul><li>1) Phase I and II reactions 2) Function: change a lipid soluble to more water soluble molecule to excrete in kidney </li></ul><ul><li>3) Possibility of active metabolites with same or different properties as parent molecule </li></ul><ul><li>Biliary Secretion – active transport, 4 categories </li></ul>
  32. 32. The enterohepatic shunt Portal circulation Liver gall bladder Gut Bile duct Drug Biotransformation; glucuronide produced Bile formation Hydrolysis by beta glucuronidase
  33. 33. EXCRETION BY OTHER ROUTES <ul><li>LUNG - For gases and volatile liquids by diffusion. </li></ul><ul><li>Excretion rate depends on partial pressure of gas and blood:air partition coefficient. </li></ul><ul><li>MOTHER’S MILK </li></ul><ul><li>a) By simple diffusion mostly. Milk has high lipid content and is more acidic than plasma (traps alkaline fat soluble substances). </li></ul><ul><li>b) Important for 2 reasons: transfer to baby, transfer from animals to humans. </li></ul><ul><li>OTHER SECRETIONS – sweat, saliva, etc.. </li></ul><ul><li>minor contribution </li></ul>
  34. 34. CLINICAL TOXICOKINETICS Quantitative Aspects of Toxicokinetics
  35. 35.
  36. 36. Plasma concentration Influence of Variations in Relative Rates of Absorption and Elimination on Plasma Concentration of an Orally Administered Chemical
  37. 37. Elimination <ul><li>Zero order: constant rate of elimination irrespective of plasma concentration. </li></ul><ul><li>First order: rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time. </li></ul><ul><li>Rate of elimination = constant (CL) x Conc. </li></ul>
  38. 38. Zero Order Elimination Pharmacokinetics of Ethanol <ul><li>Mild intoxication at 1 mg/ml in plasma </li></ul><ul><li>How much should be taken in to reach it? </li></ul><ul><li>42 g or 56 ml of pure ethanol (Vd x Conc.) </li></ul><ul><li>Or 120 ml of a strong alcoholic drink like whiskey </li></ul><ul><li>Ethanol has a constant rate of elimination of </li></ul><ul><li>10 ml/hour </li></ul><ul><li>To maintain mild intoxication, at what rate must ethanol be taken now? </li></ul><ul><li>at 10 ml/h of pure ethanol , or 20 ml/h of drink. </li></ul>RARELY DONE DRUNKENNESS
  39. 39. First Order Elimination Plasma concentration Ct = Co e -Kel.t lnCt = lnCo – Kel .t logCt = logCo - Kel . t 2.303 dC/dt = k y = b – a.x
  40. 40.
  41. 41. Time Plasma Concentration 0 1 2 3 4 5 6 1 10 100 1000 10000 Zero Order Elimination logCt = logCo - Kel . t 2.303
  42. 42. Plasma Concentration Profile after a Single I.V. Injection
  43. 43. lnCt = lnCo – Kel.t When t = 0, C = C 0 , i.e., the concentration at time zero when distribution is complete and elimination has not started yet. Use this value and the dose to calculate Vd. Vd = Dose/C 0
  44. 44. lnCt = lnCo – Kel.t When Ct = ½ C 0 , then Kel.t = 0.693. This is the time for the plasma concentration to reach half the original, i.e., the half-life of elimination. t1/2 = 0.693/Kel
  45. 45. Principle <ul><li>Elimination of chemicals from the body usually follows first order kinetics with a characteristic half-life (t1/2) and fractional rate constant (Kel). </li></ul>
  46. 46. First Order Elimination <ul><li>Clearance: volume of plasma cleared of chemical per unit time. </li></ul><ul><li>Clearance = Rate of elimination/plasma conc. </li></ul><ul><li>Half-life of elimination : time for plasma conc. to decrease by half. </li></ul><ul><li>Useful in estimating: - time to reach steady state concentration. - time for plasma conc. to fall after exposure stopped. </li></ul>
  47. 47. Rate of elimination = Kel x Amount in body Rate of elimination = CL x Plasma Concentration Therefore, Kel x Amount = CL x Concentration Kel = CL/Vd 0.693/t1/2 = CL/Vd t1/2 = 0.693 x Vd/CL
  48. 48. Principle <ul><li>The half-life of elimination of a chemical (and </li></ul><ul><li>its residence in the body) depends on its </li></ul><ul><li>clearance and its volume of distribution </li></ul><ul><li>t1/2 is proportional to Vd </li></ul><ul><li>t1/2 is inversely proportional to CL </li></ul>t1/2 = 0.693 x Vd/CL
  49. 49. Multiple dosing <ul><li>On continuous steady administration of a chemical, plasma concentration will rise fast at first then more slowly and reach a plateau, where: </li></ul><ul><li>rate of administration = rate of elimination ie. steady state is reached. </li></ul><ul><li>Therefore, at steady state: </li></ul><ul><li>Dose ( Rate of Administration ) = clearance x plasma conc. </li></ul><ul><li>or </li></ul><ul><li>steady state conc. = Dose/clearance </li></ul>
  50. 50.
  51. 51. Time plasma conc Cumulation Toxic level Single dose
  52. 52. Concentration due to a single dose Concentration due to repeated doses The time to reach steady state is ~4 t1/2’s
  53. 53. Pharmacokinetic parameters <ul><li>Vol of distribution V = DOSE / Co </li></ul><ul><li>Plasma clearance Cl = Kel .Vd </li></ul><ul><li>plasma half-life (t 1/2 ) t 1/2 = 0.693 / Kel or directly from graph </li></ul><ul><li>Bioavailability (AUC)x / (AUC)iv </li></ul>
  54. 54. But Conc. x dt = small area under the curve. For total amount eliminated (which is total given or the dose if i.v.), add all the small areas = AUC. Dose = CL x AUC and Dose x F = CL x AUC dX/dt = CL x Conc. dX = CL x Conc. x dt
  55. 55. Plasma concentration Time (hours) Bioavailability (AUC) o (AUC) iv = i.v. route oral route
  56. 56. Variability in Pharmacokinetics Daily Dose (mg/kg) Plasma Drug Concentration (mg/L) 0 5 10 15 0 10 20 30 40 50 60
  57. 57. PRINCIPLE <ul><li>The absorption, distribution and elimination of a chemical are qualitatively similar in all individuals. However, for several reasons, the quantitative aspects may differ considerably. Each person must be considered individually and treated accordingly. </li></ul>
  58. 58.
  59. 59. THE DOSE-RESPONSE RELATIONSHIP The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology , 5th ed., New York: McGraw-Hill, 1996).