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). www.freelivedoctor.com
3. Plasma Concentration Time Plasma concentration vs. time profile of a single dose of a chemical ingested orally www.freelivedoctor.com
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 www.freelivedoctor.com
12. NasopharyngealRegion 5-30 µm Trachea Bronchi Bronchioles 1-5 µm Alveolar Region 1 µm DEPOSITION OF PARTICLES IN THE RESPIRATORY SYSTEM www.freelivedoctor.com
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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 www.freelivedoctor.com
16. Bioavailability Dose Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver to systemic circulation www.freelivedoctor.com
17. Plasma concentration Time (hours) i.v. route oral route Bioavailability (AUC) o (AUC) iv www.freelivedoctor.com
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 . www.freelivedoctor.com
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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 www.freelivedoctor.com
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 www.freelivedoctor.com
25. Volume of Distribution Volume into which a drug appears to distribute with a concentration equal to its plasma concentration www.freelivedoctor.com
30. Nephron Structure The structure of the nephron (from A.C. Guyton, Textbook of Medical Physiology , Philadelphia, W.B. Saunders Co.; 1991 www.freelivedoctor.com
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32. The enterohepatic shunt Portal circulation Liver gall bladder Gut Bile duct Drug Biotransformation; glucuronide produced Bile formation Hydrolysis by beta glucuronidase www.freelivedoctor.com
36. Plasma concentration Influence of Variations in Relative Rates of Absorption and Elimination on Plasma Concentration of an Orally Administered Chemical www.freelivedoctor.com
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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 www.freelivedoctor.com
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 www.freelivedoctor.com
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 www.freelivedoctor.com
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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 www.freelivedoctor.com
51. Time plasma conc Cumulation Toxic level Single dose www.freelivedoctor.com
52. Concentration due to a single dose Concentration due to repeated doses The time to reach steady state is ~4 t1/2’s www.freelivedoctor.com
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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 www.freelivedoctor.com
55. Plasma concentration Time (hours) Bioavailability (AUC) o (AUC) iv = i.v. route oral route www.freelivedoctor.com
