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Review of Pharmacokinetics

Review of Pharmacokinetics. Jean D. Deupree, Ph.D. Department of Pharmacology University Nebraska Medical Center 3014 DRC 559-4565 jddeupre@unmc.edu. Helpful Hints. Be able to use the equations on p. 40-41. Equations will not be provided on the exam

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Review of Pharmacokinetics

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  1. Review of Pharmacokinetics Jean D. Deupree, Ph.D. Department of Pharmacology University Nebraska Medical Center 3014 DRC 559-4565 jddeupre@unmc.edu

  2. Helpful Hints • Be able to use the equations on p. 40-41. • Equations will not be provided on the exam • You will not be allowed to use a calculator on the exam • Be able to use the pharmacokinetic terms which have been defined • Be able to calculate the ionization of acid and bases in various biological media • Understand the different types of drug-drug interactions that can occur • Be able to apply the information. Exam question are not likely to be asked in the same manner as in this review • When reviewing old exams make sure you understand why the wrong answers are wrong and the right answers are right

  3. What types of molecules (charged, uncharged, chemical structural requirements) can be transported by these different mechanism? • Bulk flow • Passive diffusion • Facilitated transport • Active transport What are the differences between these transport processes?

  4. Comparison of Transport Processes

  5. Conjugate Acid Base Ionized Unionized pKa - pH = Log = Log Henderson-Hasselbalch Equation Know and be able to use these equations Weak acid Conjugate Base Acid Ionized Unionized pH - pKa = Log = Log Weak base

  6. [CB-] [A] [CB-] [A] Log ------ = pH - pKa Log ------ = pH - pKa [CB-] [A] Log ------ = [CB-] [A] Log ------ = 10,000 1 [CB- ] [A] [CB- ] [A] = How much of a weak acid (pKa = 3) will diffuse from the stomach to the plasma? Stomach pH 2 Plasma pH 7 1 A CB- + H + A 1 CB- + H + 0.1 10,000 2-3 = -1 7-3 = 4 0.1 1 = [A] + [CB-] = 1.1 [A] + [CB-] = 10,001

  7. [CA+ ] [B] [CA+] [B] Log ------ = pKa - pH Log ------ = pKa - pH [CA+] [B] Log ------ = [CA+] [B] Log ------ = [CA+] [B] [CA+] [B] = = How much of a weak base (pKa = 7) will be absorbed from the stomach? Plasma pH 7 Stomach pH 2 1B + H+ CA+ B + H+ 1 CA+ 100,000 1 7 - 2 = 5 7-7 = 0 100,000 1 1 1 1 100,000 = = [CA+] + [B] = 2 [CA+] + [B] = 100,001

  8. When is ion trapping most likely to occur in these areas? Note: You do not need to memorize the pH values for these tissues

  9. Will a weak base (pka 8) be more ionized at pH 6 or pH 8? • pH 6 • Will a weak acid (pka 4) be absorbed better from a stomach where the pH is 2 or where the pH is 3? • pH 2 • What percent of a weak acid (pKa 4 ) will be in the ionized form at pH 3 • [CB]/[A] = 0.1/1 • % in ionized form = 0.1/1.1*100 = 9%

  10. What are the advantages and disadvantages of the different routes of drug administration? • See review on page 21

  11. From which sites of drug administration do you get first-pass metabolism? First-pass hepatic metabolism?

  12. What are the factors which affect the distribution of drugs to the different tissues of the body? • Blood flow • Size of the tissue compartment • Ability of the drug to permeate the tissue • Extent of ionization in the different tissue compartments • Lipid solubility of the drug versus the lipid content of the tissue • Extent of plasma protein binding

  13. Which are the vessel rich organs and how does blood flow to an organ affect the distribution of drugs? • Vessel-rich organs • Brain • Liver • Heart • Kidney • Intermediate group • Muscle • Skin

  14. Albumin Albumin Glycoproteins Lipoproteins What plasma proteins do drugs bind to? Basic Drugs Acidic Drugs

  15. What are the characteristics of drugs which cross the placenta and enter the brain? • Drugs which are lipid soluble can cross the blood brain barrier and the placenta by passive diffusion. The more lipid soluble the drug the faster it diffuses into the brain and the faster it crosses the placenta • The more aqueous soluble drugs can only enter the brain or the fetus by active transport or facilitated diffusion. Note: Many drugs are not recognized by the transporters.

  16. What are the phase I reactions? • Oxidation • Reduction • Hydrolysis What are the phase II reactions? Conjugation

  17. What are the consequences of drug metabolism? • Pro-drug → Drug • Drug → Active and inactive metabolite • Drug → Reactive intermediate • Hydrophobic → Hydrophilic • Exposure of functional groups: -OH, -COOH, -NH2

  18. Active metabolite Conjugation Inactive metabolite Conjugation Phase I and Phase II Reactions Elimination Phase I Phase II Drug Conjugation Drug Drug Hydrophobic Hydrophilic What types of drug-drug interactions can occur?

  19. What is the principle enzymes involved in Phase I reactions and what are some of the other names for this enzyme? • Cytochrome P450 • Microsomal mixed function oxidase • Microsomal drug metabolizing enzyme

  20. Is there more than one cytochrome P450 isozymes? • How is the enzyme be regulated? • Induction • Inhibition • Note: Not all drugs will induce or inhibit the CYP isozymes, only selective isozymes will be inhibited. • NOTE: COMPETION OF ONE DRUG FOR ANOTHER ONLY BECOMES A PROBLEM IF THE DRUGS ARE IN HIGH CONCENTRATIONS. Remember for most drugs you are very low on the place of rate of elimination versus drug concentration • Note: Induction or inhibition of a CYP 450 isozyme will affect the metabolism of all drugs metabolized by that isozyme

  21. What CYP isozyme is induced by cigarette smoke? • CYP1A family • Which CYP isozyme is inhibited by grapefruit juice? • CYP 3A4 in the wall of the intestine

  22. What is the principle location of CYP isozymes? • Liver • What are the substrates, enzymes and cofactors of the CYP450 complex? • Which isozyme is responsible for metabolism of over 50% of the drugs? • CYP 3A4 • What is the significance of the CYP 2D6 enzymes? • Numerous polymorphism have been found

  23. Cytochrome P450 Enzyme Complex

  24. What are the other types of phase I reactions and what is the primary location of these enzymes? • Oxidative reactions • Flavin monooxygenases (liver) • Amine oxidase (liver and nerve endings) • Dehydrogenase (liver) • Reductive reactions • Liver • Intestinal microflora • Hydrolytic • Esterases: Plasma • Amidases: Liver

  25. What are the different types of conjugation reactions that can occur? • Glucuronidation • Sulfate conjugation • N-acetylation • Methylation • Glutathione conjugation • Amino acid conjugation What are the enzymes involved in glucuronidation and hydrolysis of the glucuronide product?

  26. UDP-glucuronyltransferase COOH O-R O Beta-glucuronidase Phase II reactionsGlucuronidation R-OH + UDP-glucuronic acid (Liver) R-O-glucuronide Bile Kidney Intestine Excretion Intestinal mucosa Intestinal bacteria R-OH + glucuronic acid

  27. How Does Age Affect Drug Metabolism? • Age • Less cyc P450 in • Very young • Elderly • Phase II reactions are usually not affected in the elderly • Decreased blood flow to liver in elderly

  28. Factors Affecting Drug Metabolism • Pharmacogenetic • Genetic differences in the activities of many metabolic enzymes • Altered activity of CPY enzymes and enzymes involved in conjugation • 2D6 enzymes • N-acetyltransferase: Slow vs fast acetylators

  29. Glomerular Filtration Tubular Reabsorption Nephron Tubular Secretion Excretion = glomerular filtration - tubular reabsorption + tubular secretion - passive reabsorption +passive secretion What factors determining the amount of drug excreted in the urine?

  30. How do you speed up the renal elimination of a weak acid? • Make the urine alkaline

  31. How are drugs or metabolites excreted from liver to bile? • Passive diffusion • Transporters for • anions • bile salts • cations • neutral organic compounds • How do you enhance biliary excretion? • polar groups • high molecular weight • Conjugation add polar groups and molecular weight

  32. What drugs go through the enterohepatic recirculation pathway? • Drugs which enter the bile and are: • Lipid soluble enough to be reabsorbed from the wall of the gut • Hydrolyzed in the gut and then reabsorbed • Transported by transporters across the wall of the gut

  33. What is the major route by which drugs are eliminated from the body? • Kidney • What are the minor routes? • bile • skin • lungs • sweat glands • saliva • breast milk

  34. What are the basic types of pharmacokinetic drug- interactions? • Involving metabolism • Induction of cyc P450 enzymes • Inhibition of cyc P450 enzymes • Competition of two drugs for the same enzyme • Depletion of endogenous compounds used in conjugation reactions • Displacement from albumin • Competition for transporters • Blood flow to an organ • Changes in pH of a body of fluid

  35. 5 4 Peak Drug Level 3 2 1 Time to Peak Drug Level 0 0 2 4 6 8 10 12 Serum Concentration (mg/ml) Time After Drug Administration (hr)

  36. 5 4 3 Serum Concentration (mg/ml) 2 1 0 0 2 4 6 8 10 12 Time After Drug Administration (hr) Duration of Therapeutic Effect Therapeutic Threshold

  37. 5 4 3 Serum Concentration (mg/ml) 2 1 0 0 2 4 6 8 10 12 Time After Drug Administration (hr) Toxic Effect Therapeutic Window Therapeutic Effect

  38. What is the difference between therapeutic window and therapeutic index? • Therapeutic window is the plasma concentration range where therapeutic effect occurs without toxic effects • Therapeutic index is: TD50/ED50

  39. AUC for route being studied AUC after IV administration F = How do you determine bioavailability? What factors will alter bioavailability?

  40. Xo mg Cp (mg/ml) Vd (L) = What is the Volume of Distribution of a drug?

  41. 10 8 Cp 6 Plasma Drug Concentration (μg/ml) 4 2 0 10 20 30 40 50 60 Time (Hours) How do you measure the concentration of drug in the plasma at time T = 0?

  42. What does it mean if a drug has the following Vd in a 70 kg person? • 500 L • 10 L • 35 L • 42 L

  43. What is meant by t1/2? • How many half-lives does it take for the drug concentration to reach steady-state? • 4 to 5 half-lives • How many half-lives does it take for the drug to be eliminated from the body? • 4 to 5 half-lives • What is kel? • Rate constant for elimination • What are the units for kel? • 1/time • How does kel change with plasma concentration? • It remains constant at low concentrations of drug

  44. 100 80 60 Plasma Drug Concentration (μg/ml) 40 20 2 4 6 8 Time (Hrs) Is this drug being eliminated by first order or zero order kinetics? Zero order What is the half-life of this drug? Half-life changes with plasma concentration If you double the dose how long does it take to eliminate the drug from the body? Twice as long What happens to steady state plasma levels if you double the dose? Greater than 2x plasma level

  45. Effects of Doubling DoseZero Order Kinetics 25 20 Plasma Concentration (mg/L) 15 10 8 16 24 32 40 48 56 64 72 80 88 96 Time (hrs) NOTE: Drug is entering the body faster than it leaves the body

  46. 10 8 6 Plasma Drug Concentration (μg/ml) 4 2 0 10 20 30 40 50 60 Time (Hours) Is this drug being eliminated by first order or zero order kinetics? 1st order What is the half-life of this drug? 10 hours If you double the dose how long does it take to eliminate the drug from the body? 4 to 5 half-lives or 40-50 hours --- time is independent of plasma levels What happens to steady state plasma levels if you double the dose? Plasma levels double

  47. Effects of Doubling Dose1st Order Kinetics 8 6 Plasma Concentration (mg/L) 4 2 8 16 24 32 40 48 56 64 72 80 88 96 Time (hrs) Note: Drug enters body at the same rate it is leaving the body

  48. Is this drug being eliminated by first order or zero order kinetics? 1st order What is the half-life of this drug? 10 hours How long will it take to reach steady state plasma concentration if this drug is given by continual IV infusion? 40 to 50 hours

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