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ESTIMATE OF CHEMICALS IN USE TODAY

ROUTES OF ELIMINATION OF XENOBIOTICS. ESTIMATE OF CHEMICALS IN USE TODAY. Type Number. Active ingredients in pesticides 1,500 Pharmaceutical products 6,000 Food additives (with nutritional value) 2,500 Food additives (promote product life) 3,000

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ESTIMATE OF CHEMICALS IN USE TODAY

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  1. ROUTES OF ELIMINATION OF XENOBIOTICS ESTIMATE OF CHEMICALS IN USE TODAY TypeNumber Active ingredients in pesticides 1,500 Pharmaceutical products 6,000 Food additives (with nutritional value) 2,500 Food additives (promote product life) 3,000 Additional chemicals (household, etc) 50,000 Natural pesticides 10,000

  2. Amount of chemical exposure in the average diet Typemg daily Natural pesticides and breakdown products 1,500 Products resulting from cooking 2,000 Synthetic pesticides 0.09

  3. I. RENAL EXCRETION Mechanisms of Renal Excretion • filtration • active tubular secretion • tubular reabsorption • biotransformation Physicochemical Determinants • molecular size • (MW < 5000) • lipophilicity • ionization • protein binding From Mehvar et al. JPharmSci 83:1495, 1994.

  4. II. HEPATIC ELIMINATION A. BIOTRANSFORMATION B. BILIARY EXCRETION Reproduced from: Levine RR. Pharmacology: Drug Actions and Reactions, 4th edition, Little, Brown, and Company, p. 146

  5. Adapted from : Friedman Sl. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 275:2247-2250, 2000.

  6. Reproduced from: Klassen CD, Watkins JB. Pharmacol Rev 36:1, 1984

  7. 1. MECHANISMS OF BILIARY CLEARANCE a. Classification of Agents ClassBile:Plasma RatioExamples A ~1 Na+, K+, CL-, glucose B 10-1000 bile acids, bilirubin, xenobiotics C <1 cholesterol, phospholipids, sucrose, albumin Cholephil: An agent whose bile:plasma ratio >1

  8. b. Diversity of Transporters From: Tirona RG, Kim RB. Advanced Drug Delivery Reviews 54:1343-1352, 2002

  9. 1. MECHANISMS OF BILIARY CLEARANCE a. Classification of Agents b. Diversity of Transporters c. Factors Influencing Biliary Excretion Physicochemical Factors Physiological Factors Pharmacological Factors

  10. 1. MECHANISMS OF BILIARY CLEARANCE a. Classification of Agents b. Variation of Transporters c. Factors Influencing Biliary Excretion • Physicochemical Factors • Molecular weight (400-500) Influence of molecular weight on the biliary excretion of several cephalosporins in the rat. Dose excreted was determined after parenteral administration in bile cannulated rats. Data from: Wright WE, Line VD. Biliary excretion of cephalosporins in rats: influence of molecular weight. Antimicrob Ag Chemother 17:842-846, 1980.

  11. 1. MECHANISMS OF BILIARY CLEARANCE a. Classification of Agents b. Variation of Transporters c. Factors Influencing Biliary Excretion • Physicochemical Factors • Molecular weight (400-500) • Polarity • Protein binding

  12. 1. MECHANISMS OF BILIARY CLEARANCE a. Classification of Agents b. Variation of Transporters c. Factors Influencing Biliary Excretion • Physicochemical Factors • Molecular weight (400-500) • Polarity • Protein binding • Physiological Factors • Species • Age • Sex(?), pregnancy(?)

  13. 1. MECHANISMS OF BILIARY CLEARANCE a. Classification of Agents b. Variation of Transporters c. Factors Influencing Biliary Excretion • Physicochemical Factors • Molecular weight (400-500) • Polarity • Protein binding • Physiological Factors • Species • Age • Sex(?), pregnancy(?) • Pharmacological Factors • Chlorotoxicants • Hepatotoxicants • Microsomal enzyme inducers

  14. 2. IMPACT OF ENTEROHEPATIC RECIRCULATION ON THE DISPOSITION OF XENOBIOTICS GI Tract LIVER Bile Duct Systemic Circulation Drug Drug Portal Vein Drug Drug

  15. 2. IMPACT OF ENTEROHEPATIC RECIRCULATION ON THE DISPOSITION OF XENOBIOTICS Effect of Interruption of Enterohepatic Cycling on Drug Elimination ConditionHalf-life Digitoxin 6 days Digitoxin + cholestyramine 4.5 days Dapsone 20.5 hr Dapsone + charcoal 10.8 hr

  16. EXAMPLES OF XENOBIOTICS EXCRETED INTO BILE AND SUBJECT TO ENTEROHEPATIC RECIRCULATION CompoundSpecies in bile Cefoperazone unknown Estradiol conjugates Valproic acid glucuronide Chloramphenicol glucuronide Digitoxin conjugates Spironolactone metabolites Imipramine parent and desmethyl

  17. Plasma concentration profile for sulindac and metabolites prior to and after consumption of breakfast. Sulindac (circles) was administered as a dose of 200 mg to a subject. The sulfone (squares) and sulfide (triangles) metabolites were also determined during the 12 to 36 hr period. Note re-entry peak after breakfast at 22 hr. Reproduced with permission from Dobrinska MA. J Clin Pharmacol 29:577, 1989.

  18. II. HEPATIC ELIMINATION III. PULMONARY EXCRETION BLOOD: ALVEOLAR AIR ETHANOL = 2100:1 From: Raufman J-P, et al. Ann Intern Med 118:488, 1993

  19. IV. OTHER ROUTES • Hair • drugs • heavy metals • B. Tears Rifampin + = http://www.hair-drug-tests.com/?portalid=LOOHDT Soft contact lens

  20. V. QUANTIFICATION OF RATE OF ELIMINATION A. Half-life

  21. Uses of half-life: 1. Time to steady-state

  22. Uses of half-life: 1. Time to steady-state 2. Time for elimination 3. Dosing interval Reproduced from: Shargel L, Yu ABC. Applied Biopharma- ceutics and Pharmacokinetics, 4th edition.

  23. V. QUANTIFICATION OF RATE OF ELIMINATION A. Half-life B. Clearance

  24. DRUG RESPONSE DRUG CONCENTRATION DISTRIBUTION ABSORPTION ELIMINATION RENAL EXCRETION BILIARY EXCRETION METABOLISM DISEASE GENETICS PHYSIOLOGICAL VARIATIONS ENVIRONMENTAL EXPOSURE

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