1. Distribution From A Physiologic Perspective Problems / Questions Related to Introduction Distribution From A Physiologic Perspective] Five “Distribution Problems” are provided starting at slide 21. Not all of these problems will be completed in class … but you are expected to work through them on your own. Objectives

2. Opening Question: Mr. JR receives 500 mg of Levofloxacin by intravenous bolus (over 1 minute) and the serum concentration is measured immediately and found to be 5.0 mg/L. What is the apparent volume of distribution? What percent of drug is located in serum?

3. Distribution Where does drug go? Objective Review Basic Principles related to drug & chemical / metabolite distribution in the body Develop a definition for Volume of Distribution

4. Where does the drug go? Is it confined to blood or is it mostly in the blood or is it largely confined to tissues?

5. Facts and Figures Body Weights Actual vs Ideal (IBW) Male: 50 kg + (2.5 kg/inch over 5 ft) Female: 45.5 kg + (2.3 kg / inch over 5 ft) Blood Volume (L) ~ 8% of IBW Body water (L) ~60% of IBW

6. Barriers to Distribution 1.GI Tract  Intestinal wall prevents absorption … not all drugs are absorbed 2.Vascular walls  limits “escape” from serum / blood 3.Cellular walls  limits “free” movement within the body Extra-cellular Water ~ 15 L Intra-cellular Water ~ 25 L  RBC’s, ~ 45% of whole blood Plasma or Serum ~ 55%  Whole Blood ~ 5 L

7. Body Water 1 1.Skelton, H. Arch Int. Med 1927; 40: 140. Tissue% Water %Weight Water per 70 kg ( L ) Skin72 189.1 Muscle75 42 22.1 Brain75 21.1 Skelton22 162.5 Adipose10~100.7 Other 126.5 Total100 42

8. General Principles of Distribution 10 L 1000 mg If you add 1000 mg of a drug to 10 L of water, what is the final concentration? Following complete mixing Concentration (C) = 1000 mg/ 10L = 100 mg/L C = Amount / volume Volume = Amount / C

9. General Principles of Distribution 10 L 1000 mg If you add 1000 mg of a drug to 10 L of water, what is the final concentration? Could the concentration change as a function of time after addition? C = Amount / volume Volume = Amount / C If you knew that you had added 1000 mg of drug and then drew a sample from a corner of the vessel before complete mixing occurred, what would you conclude?

10. General Principles of Distribution 10 L 1000 mg Again you add 1000 mg of a drug to 10 L of water, but now there is some charcoal in the water that may bind the drug. The observed concentration after complete mixing is 50 mg/L Since Volume = Amount / C then the apparent volume of distribution is: = 1000 mg/50 mg/L = 20L …??? BUT The real volume is 10L Charcoal

11. General Principles of Distribution 10 L 1000 mg Again you add 1000 mg of a drug but this time in addition to the charcoal and 10L of water there is 1 L of oil. You measure the concentration in the oil (150 mg/L) and in the water (25 mg/L). Now calculate the volume: Based on the concentration in the water Volume = Amount / C then the apparent volume of distribution is: = 1000 mg/25 mg/L = 40L Charcoal 1L

12. Again you add 1000 mg of a drug but this time in addition to the charcoal and 10L of water there is 1 L of oil. You measure the concentration in the oil (150 mg/L) and in the water (25 mg/L). General Principles of Distribution 10 L 1000 mg Now calculate the volume: Based on the concentration in the oil Volume = Amount / C then the apparent volume of distribution is: = 1000 mg/150 mg/L = 6.66 L Charcoal 1L

13. Mass Balance Water: Concentration 25 mg/L True Volume: 10L Amount of Drug = 250 mg Apparent Volume = 40L Oil: Concentration 150 mg/L True Volume: 1L Amount of Drug = 150 mg Apparent Volume = 6.66 L Charcoal:(therefore) Amount = 600 mg General Principles of Distribution 10 L 1000 mg Charcoal 1L

14. Conclusions 1.The calculated Apparent Volume depends on the fluid being sampled. 2.The volume depends on the host, and the physical/chemical properties of the drug or metabolite 3.The calculated Apparent Volume rarely reflects a real physiologic volume. General Principles of Distribution 10 L 1000 mg Charcoal 1L

15. …so what is the Apparent Volume of Distribution? … it is the volume of sampled fluid need to account for the total amount of drug in the body … at distribution equilibrium … (following complete mixing). The volume is not associated with a particular space or anatomical area or tissue. It is a proportionality constant relating concentration and amount in the body. General Principles of Distribution 10 L 1000 mg Charcoal 1L

16. …so, if it is not real, how useful is it? Uses: It tells us how much drug must be added to the body so as to achieve a specified concentration in the sampled fluid. In a general way it tells us where the drug is stored in the body or where it might be found. General Principles of Distribution 10 L 1000 mg Charcoal 1L

17. L/70 kg 50,000 20,000 10,000 5,000 1,000 500 100 50 10 5 General Principles of Distribution Quinacrine Chloroquine Nortriptyline Digoxin Propranolol Quinidine Quinolones (1- 2 L/kg), Tetracycline Phenobarbital Phenytoin Theophylline (0.45 L/kg) Aminoglycodises (0.25 L/kg) ASA Warfarin

18. Question: If the drug is distributing to total body water, why are there large differences in the volume for different drugs? General Principles of Distribution Physical Chemical properties of the drug High molecular weight (mabs) and even ICG (MW = 775) are confined to plasma volume. Ions (Cl -, Br - ) rapidly distribute throughout extra-cellular fluid but do not easily cross cell membranes. Other Ions (K +, Ca 2+) are actively transported across membranes. Potassium is predominately intra-cellular. Protein Binding

19. Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. In blood, drugs often bind to albumin. The unbound (free) drug can diffuse out of the blood, into the extra-cellular water and often into cells (intra-cellular water). Equilibrium is established General Principles of Distribution

20. Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. The equilibrium between Bound & Free remains in place. It is also assumed that at equilibrium the free concentration is equal in all tissues General Principles of Distribution

21. Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. If a drug is highly bound within tissues, the equilibrium established between bound and free will find the majority of the drug in tissues, (based on binding and mass). General Principles of Distribution

22. Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. Protein binding in blood will keep drug in blood. However, since tissue mass exceeds blood volume, any binding in tissues will shift the equilibrium toward drug in tissues. General Principles of Distribution

23. Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. The volume of distribution of a drug can be viewed as a relationship between tissue binding and binding to protein within the blood. If a drug is highly protein bound within blood but has little tissue binding, the volume of distribution will be small (~10L – e.g. warfarin). General Principles of Distribution

24. Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. Even if a drug is highly protein bound within blood but also has high tissue binding, the volume of distribution will be large. General Principles of Distribution

25. Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. The volume of distribution of a drug can be viewed as a relationship between tissue binding and binding to protein within the blood. General Principles of Distribution Vd TOTAL = V B + V T (f B /f T ) Where V B is blood volume ~ 5L and V T is body water (between 30-50 L). f B and f T is the fraction unbound in tissue and in blood

26. Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. The volume of distribution of a drug can be viewed as a relationship between tissue binding and binding to protein within the blood. General Principles of Distribution Vd TOTAL = V B + V T (f B /f T ) Where V B is blood volume ~ 5L and V T is body water (between 30-50 L). If f B is 5% (free in blood or plasma) and f T is 100% (free in issues – no binding) The final volume is 5L of blood volume plus ~2.5L of tissue volume. 7.5L total.

27. Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. The volume of distribution of a drug can be viewed as a relationship between tissue binding and binding to protein within the blood. General Principles of Distribution Vd TOTAL = V B + V T (f B /f T ) Where V B is blood volume ~ 5L and V T is body water (between 30-50 L). If f B is 5% (free in blood or plasma) But f T is 1% (free in issues – 99% binding) The final volume is 5L of blood volume plus ~250 L of tissue volume. 255L total.

28. Vd TOTAL = V B + V T (f B /f T ) This makes the assumption that the drug may distribute to all places in the body where water exists and this may not be true if there is active transport in or out of a particular tissue. eg. BBB etc. Effect of Protein Binding on Volume of Distribution General Principles of Distribution

29. Observe the Effect of Protein Binding on Volume of Distribution of Propranolol For propranolol as the free fraction increases from ~5% to ~30% Volume (Vd) increases from ~125 L to ~800 L. 6-fold increases in both FF and Vd. Open circles – Liver disease patients General Principles of Distribution

30. L/70 kg 50,000 20,000 10,000 5,000 1,000 500 100 50 10 5 General Principles of Distribution Quinacrine Chloroquine Nortriptyline Digoxin Propranolol Quinidine Quinolones (1- 2 L/kg), Tetracycline Phenobarbital Phenytoin Theophylline (0.45 L/kg) Aminoglycodises (0.25 L/kg) ASA Warfarin Five Examples: Example 5:Cyclosporin … 3000L Example 2:Ciprofloxacin … 120L Example 1:Levofloxacin … 100L Example 4:Levofloxacin … 83.3L Example 3:Theophylline … 36L Notice that the Volume of distribution is different for all drugs and will also be different for each patient (levo).

31. Distribution Problems Five Examples: Example 1:Levofloxacin Calculate Volume Example 2:Ciprofloxacin Given Volume, Calculate Concentration Example 3:Theophylline Calculate Volume …then predict new dose Example 4:Levofloxacin Example 5:Cyclosporin M ale A cute C ommunity Acquired Pneumonia

32. General Principles of Distribution Summary 1.The calculated apparent Volume depends on the fluid being sampled. 2.Drugs can go anywhere (phys.-chem. prop.) leaving extra-cellular water to distribute into bone, fat or … anywhere, any tissue. 3.The apparent Volume depends on the host, and the physical/chemical properties of the drug or metabolite. 4.The calculated apparent Volume rarely reflects a real physiologic volume. 5.The minimum volume* of distribution is vascular volume (8% IBW: 6’ ♂ = 6.4L). 6.There is no maximum volume*.

33. Volume of Distribution Blood Liver Kidney GI Tract Oral Dose IV Dose First Example:Levofloxacin

34. Distribution Problem 1 Calculate Volume Male with Pneumonia Age:45 yr Weight: 80 kg Drug:Levofloxacin Observe:Serum levofloxacin concentration following i.v. bolus of 500 mg 5  g/mL (mg/L) Additional Information: Blood Volume:8% of body weight Hematocrit:0.45 M ale A cute C ommunity Acquired Pneumonia

35. Distribution Problem 1 Questions 1.What is the Volume of distribution of levo? 2.Where in the body does levo appear to be located? What percent is located in the Serum? 3.If the serum levo concentration is at the mid-point of target…3  g/mL (a)how much drug is in the serum? (b)what is the total amount of drug in your patient (MAC)? M ale A cute C ommunity Acquired Pneumonia

36. Distribution Problem 1 Answers. 1.What is the Volume of distribution of levo? Dose = Initial [ ] = Levo Volume:= 2.Proportion in Serum: = M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

37. Distribution Problem 1 Answers. 1.What is the Volume of distribution of levo? Dose = 500 mg Initial [ ] = 5  g/mL (mg/L) Levo Volume:= Dose / Conc = 500 / 5 = 100 L 2.Proportion in Serum: = M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

38. Distribution Problem 1 Answers. 2.Proportion in Serum: Weight :80 kg Levo Volume:500 mg/ 5 mg/L Blood Volume:8% of body weight Hematocrit:0.45 Blood volume:= Serum (55%):= Levo Volume:= Proportion in Serum: = M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

39. Distribution Problem 1 Answers. 2.Proportion in Serum: Weight :80 kg Levo Volume:500 mg/ 5 mg/L Blood Volume:8% of body weight Hematocrit:0.45 Blood volume:= 0.08 x 80 kg = 6.4 L Serum (55%): =6.4 x 0.55 = 3.5 L Levo Volume: = 500 mg/ 5 mg/L = 100 L Proportion in Serum: = M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

40. Distribution Problem 1 Answers. 2.Proportion in Serum: Weight :80 kg Levo Volume:500 mg/ 5 mg/L Blood Volume:8% of body weight Hematocrit:0.45 Blood volume:= 0.8 x 80 kg = 6.4 L Serum (55%): =6.4 x 0.55 = 3.5 L Levo Volume: = 500 mg/ 5 mg/L = 100 L Proportion in Serum: = 3.5 L/100.0 L = 3.5% M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

41. Distribution Problem 1 Answers. 3.If the serum levofloxacin concentration is at the mid-point of target … ~ 3mg/L … (a)how much drug is in the serum? (b)what is the total amount of drug in MAC? Therapeutic Range:5 - 1  g/mL = mg/L mid point: 3 mg/L Amount in body at equilibrium: = Amount in serum: = M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

42. Distribution Problem 1 Answers. 3.If the serum levofloxacin concentration is at the mid-point of target … ~ 3mg/L … (a)how much drug is in the serum? (b)what is the total amount of drug in MAC? Therapeutic Range:5 - 1  g/mL = mg/L mid point: 3 mg/L Amount in body at equilibrium: = 3 mg/L x 100.0 L = 300 mg Amount in serum: = 3 mg/L x 3.5 L = 10.5 mg Percent in serum:= 10.5 mg/ 300 mg = 3.5% M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

43. Levofloxacin Distribution Problem 1 Review Answers. Body Weight:80 kg Blood Volume:8% of body weight Serum is 55% of Blood Serum = (0.08) x (0.55) x (80) = 3.52 L Serum conc.= 3  g/mL = 3 mg/L Amount in Serum: = (3.5 L) x 3 mg/L) = 10.5 mg Amount in Body, based on volume of 100 L = (3) x (100) = 300 mg Percent in Serum: 10.5 mg / 300 mg = 3.5% Volume 100 L 100 L/80kg = 1.2 L/kg Recall Levo monograph indicated volume was between 74 & 112 L.

44. Volume of Distribution Blood Liver Kidney GI Tract Oral Dose IV Dose Second Example:Ciprofloxacin

45. Distribution Problem 2 This time … given Volume Male with Pneumonia Age:45 yr Weight: 80 kg Drug:Ciprofloxacin Goal:Serum ciprofloxacin concentrations ranging 3 - 4  g/mL (target) Additional Information: Cipro Volume: 1.5 L/kg Blood Volume:8% of body weight Hematocrit:0.45 M ale A cute C ommunity Acquired Pneumonia

46. Distribution Problem 2 Questions 1.What dose should be given to MAC to achieve a peak concentration of between 3 and 4  g/mL? 2.What percent is located in the Serum? 3.If the serum cipro concentration is at the mid-point of target…3.5  g/mL (a)how much drug is in the serum? (b)what is the total amount of drug in MAC? M ale A cute C ommunity Acquired Pneumonia

47. Distribution Problem 2 Answers. 1.What dose should be given to MAC to achieve a peak concentration of between 3 and 4  g/mL? Cipro Volume:1.5 L/kg Pt weight:80 kg 6.4 x 0.55 = 3.5 L Cipro Volume (L):= M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

48. Distribution Problem 2 Answers. 1.What dose should be given to MAC to achieve a peak concentration of between 3 and 4  g/mL ? Cipro Volume:1.5 L/kg Pt weight:80 kg 6.4 x 0.55 = 3.5 L Cipro Volume (L):= 1.5 L/kg x 80 kg = 120.0 L Peak target [ ] mg/L= 3  g/mL Req. Cipro Dose= M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

49. Distribution Problem 2 Answers. 1.What dose should be given to MAC to achieve a peak concentration of between 3 and 4  g/mL? Cipro Volume:1.5 L/kg Pt weight:80 kg 6.4 x 0.55 = 3.5 L Cipro Volume (L):= 1.5 L/kg x 80 kg = 120.0 L Peak target [ ] mg/L= 3  g/mL (mg/L) Req. Cipro Dose= 3 mg/L x 120 L = 360 mg M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

50. Distribution Problem 2 Answers. 1.What dose should be given to MAC to achieve a peak concentration of between 3 and 4  g/mL? Cipro Volume:1.5 L/kg Pt weight:80 kg 6.4 x 0.55 = 3.5 L Cipro Volume (L):= 1.5 L/kg x 80 kg = 120.0 L Peak target [ ] mg/L= 4  g/mL (mg/L) Req. Cipro Dose= 4 mg/L x 120 L = 480 mg M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

51. Distribution Problem 2 Answers. 1.What dose should be given to MAC to achieve a peak concentration of between 3 and 4  g/mL? Peak target 3 mg/L= Dose = 360mg Peak target 4 mg/L= Dose = 480mg Common dose of Cipro IV? M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

52. Distribution Problem 2 Answers. 1.What dose should be given to MAC to achieve a peak concentration of between 3 and 4  g/mL? Peak target 3 mg/L= Dose = 360mg Peak target 4 mg/L= Dose = 480mg Common dose of Cipro IV? 400 mg M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

53. Distribution Problem 2 Answers. 2.What percent is located in the Serum? Weight :80 kg Cipro Volume:1.5 L/kg Blood Volume:8% of body weight Hematocrit:0.45 Blood volume:0.8 x 80 kg = 6.4 L Serum vol. (55%):6.4 x 0.55 = 3.5 L Cipro Volume:1.75 L/kg x 80 kg 140.0 L Proportion in Serum: 3.5 L/140.0 L = 2.5% M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

54. Distribution Problem 2 Answers. 2.What percent is located in the Serum? Weight :80 kg Cipro Volume:1.5 L/kg Blood Volume:8% of body weight Hematocrit:0.45 Blood volume:0.08 x 80 kg = 6.4 L Serum vol. (55%):6.4 x 0.55 = 3.5 L Cipro Volume:1.5 L/kg x 80 kg 120.0 L Proportion in Serum: 3.5 L/120.0 L = 2.9% M ale A cute C ommunity Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

55. Ciprofloxacin Distribution Problem 2 Review Answers. Body Weight:80 kg Blood Volume:8% of body weight Serum is 55% of Blood Serum = (0.08) x (0.55) x (80) = 3.52 L Serum conc.= 3  g/mL = 3 mg/L Amount in Serum: = (3.5 L) x 3 mg/L) = 10.5 mg Amount in Body, based on volume of 120 L = (3) x (120) = 360 mg (Dose= 400 mg) Percent in Serum: 10.5 mg / 360 mg = 2.9% Volume 1.5 L/kg 120.0 L

56. Volume of Distribution Blood Liver Kidney GI Tract Oral Dose IV Dose Third Example:Theophylline

57. Distribution Problem 3 Male Asthmatic Age:45 yr Weight: 80 kg Drug:Theophylline Goal:Serum theophylline in the therapeutic range 10 – 20  g/mL Additional Information: Initial Theophylline Dose of 300 mg produces a peak following a bolus iv dose of 8.33 mg/L. S evere A sthmatic M ale

58. Distribution Problem 3 Questions 1.What is the volume of distribution of theophylline? 2.What percent is located in the Serum? 3.If we need to produce a peak serum theophylline concentration near the mid-point of target… (~15 mg/L), what should the dose be? S evere A sthmatic M ale

59. Distribution Problem 3 Answers. 1.What is the volume of distribution of theophylline? Theophylline Dose= 300 mg Peak [ ] mg/L= 8.33 mg/L. 0.55 = 3.5 L Theophylline Volume:= Vol. Expressed as L/kg:= S evere A sthmatic M ale Equations Conc = Dose / V V = Dose/Conc

60. Distribution Problem 3 Answers. 1.What is the volume of distribution of theophylline? Theophylline Dose= 300 mg Peak [ ] mg/L= 8.33 mg/L. 0.55 = 3.5 L Theophylline Volume: = 300 mg / 8.33 mg/L = 36 L Expressed as L/kg: = 36 L / 80 kg = 0.45 L/kg S evere A sthmatic M ale Equations Conc = Dose / V V = Dose/Conc

61. Distribution Problem 3 Answers. 2.Proportion in Serum? Weight :80 kg Theophylline Volume: 0.45 L/kg Blood Volume:8% of body weight Hematocrit:0.45 Blood volume:0.8 x 80 kg = 6.4 L Serum (55%):6.4 x 0.55 = 3.5 L Theophylline Volume:0.45 L/kg x 80 kg 36.0 L Proportion in Serum: 3.5 L / 36.0 L = 9.8% S evere A sthmatic M ale Equations Conc = Dose / V V = Dose/Conc

62. Distribution Problem 3 Answers. 2.Proportion in Serum? Weight :80 kg Theophylline Volume: 0.45 L/kg Blood Volume:8% of body weight Hematocrit:0.45 Blood volume:0.08 x 80 kg = 6.4 L Serum (55%):6.4 x 0.55 = 3.5 L Theophylline Volume:= 0.45 L/kg x 80 kg = 36.0 L Proportion in Serum: = 3.5 L / 36.0 L = 9.8% S evere A sthmatic M ale Equations Conc = Dose / V V = Dose/Conc

63. Distribution Problem 3 Answers. 3.If we need to produce a peak serum theophylline concentration near the mid-point of target… (~15 mg/L), what should the dose be? Therapeutic Range:10 – 20  g/mL = mg/L mid point: 15 mg/L Amount in body at 15 mg/L: 15 mg/L x 36.0 L = 540 mg Dose: 15 mg/L x 3.5 L = 52.5 mg S evere A sthmatic M ale Equations Conc = Dose / V V = Dose/Conc

64. Distribution Problem 3 Answers. 3.If we need to produce a peak serum theophylline concentration near the mid-point of target… (~15 mg/L), what should the dose be? Therapeutic Range:10 – 20  g/mL = mg/L mid point: 15 mg/L Amount in body at 15 mg/L: 15 mg/L x 36.0 L = 540 mg Dose:actual dose??? 540 mg peak of 15 mg/L S evere A sthmatic M ale Equations Conc = Dose / V V = Dose/Conc

65. Distribution Problem 3 Answers. 3.If we need to produce a peak serum theophylline concentration near the mid-point of target… (~15 mg/L), what should the dose be? Dose:actual dose??? 540 mg= peak of 15 mg/L 600 mg= peak conc? = 600 mg / 36 L = 16.6 mg/L 500 mg= peak conc? = 500 mg / 36 L = 13.9 mg/L S evere A sthmatic M ale Equations Conc = Dose / V V = Dose/Conc

66. Distribution Problem 3 Answers. Body Weight:80 kg Blood Volume:8% of body weight Serum is 55% of Blood Serum = (0.08) x (0.55) x (80) = 3.52 L Serum conc.= 15  g/mL = 15 mg/L Amount in Serum: = (3.5 L) x 15 mg/L) = 52.5 mg Amount in Body, based on volume of 36 L = (15) x (36) = 540 mg Percent in Serum: 52.5 mg / 540 mg = 9.8% Volume 0.45 L/kg 36.0 L

67. Volume of Distribution Blood Liver Kidney GI Tract Oral Dose IV Dose Fourth Example:Levofloxacin in a different patient

68. Distribution Question Example 4 Mr. JR, as 45 yr old male weighing 80 kg and appears to have Community Acquired Pneumonia. He is prescribed 500 mg of levofloxacin, once per day for 7 days. Immediately following the first dose, given by I.V. bolus, a plasma concentration is measured as 6.0 mg/L. 1.Calculate the apparent volume of distribution. 2.What percent of the drug is in plasma? 3.Other Questions about “Distribution”?

69. Distribution Question Example 4 Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6.0 mg/L. 1.Calculate the apparent volume of distribution. Conc = Dose / Volume Volume = Dose / Conc = 500 mg / 6.0 mg/L = Equations Conc = Dose / V V = Dose/Conc

70. Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6.0 mg/L. 1.Calculate the apparent volume of distribution. Conc = Dose / Volume Volume = Dose / Conc = 500 mg / 6.0 mg/L = 83.33 liters Expressed per kg of body weight = Equations Conc = Dose / V V = Dose/Conc Notice that this volume is slightly different than the 100 L calculated for a different patient Distribution Question Example 4

71. Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6.0 mg/L. 1.Calculate the apparent volume of distribution. Conc = Dose / Volume Volume = Dose / Conc = 500 mg / 6.0 mg/L = 83.33 liters Expressed per kg of body weight = 83.33 liters / 80 kg =1.04 L/kg Equations Conc = Dose / V V = Dose/Conc Distribution Question Example 4

72. Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6.0 mg/L. 1.Calculate the apparent volume of distribution. Volume = 83.33 liters Vol per kg of body weight = 1.04 L/kg 2.What percent of the drug is in plasma? Blood is ~8% of body weight Mr. JR weighs 80 kg. Blood Volume is ~ 6.4 L Plasma volume is ~55% of blood volume. Plasma volume = 6.4 L x 0.55 = 3.52 L. Equations Conc = Dose / V V = Dose/Conc Distribution Question Example 4

73. Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6.0 mg/L. 2.What percent of the drug is in plasma? Plasma volume= 6.4 L x 0.55 = 3.52 L. Conc in plasma= 6.0 mg/L Amount in plasma= Equations Conc = Dose / V V = Dose/Conc Distribution Question Example 4

74. Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6.0 mg/L. 2.What percent of the drug is in plasma? Plasma volume= 6.4 L x 0.55 = 3.52 L. Conc in plasma= 6.0 mg/L Amount in plasma= 3.52 L x 6.0 mg/L = 21.12 mg. How much is in the body? volume distrib.= 83.33 L Conc in plasma= 6.0 mg/L Amount in body = Equations Conc = Dose / V V = Dose/Conc Distribution Question Example 4

75. Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6.0 mg/L. 2.What percent of the drug is in plasma? Plasma volume= 6.4 L x 0.55 = 3.52 L. Conc in plasma= 6.0 mg/L Amount in plasma= 3.52 L x 6.0 mg/L = 21.12 mg. How much is in the body? volume distrib.= 83.33 L Conc in plasma= 6.0 mg/L Amount in body= 6.0 mg/L x 83.33L = 500 mg (dose) Equations Conc = Dose / V V = Dose/Conc Distribution Question Example 4

76. Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6.0 mg/L. 2.What percent of the drug is in plasma? Amount in plasma= 3.52 L x 6.0 mg/L = 21.12 mg. Amount in body = 6.0 mg/L x 83.33L = 500 mg (dose) Proportion in plasma ? = Equations Conc = Dose / V V = Dose/Conc Distribution Question Example 4

77. Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6.0 mg/L. 2.What percent of the drug is in plasma? Amount in plasma= 3.52 L x 6.0 mg/L = 21.12 mg. Amount in body = 6.0 mg/L x 83.33L = 500 mg (dose) Proportion in plasma = 21.12 mg / 500 mg = 0.042 = 4.2% Equations Conc = Dose / V V = Dose/Conc Distribution Question Example 4

78. Volume of Distribution Blood Liver Kidney GI Tract Oral Dose IV Dose Fifth Example:Cyclosporin

79. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. Immediately after the dose a blood sample is taken and the blood concentration is measured as 200 ng/mL. (a)What is the apparent volume of distrib? (b)What percent of CsA in the body is located in blood / plasma in this patient? A Fifth Example - cyclosporin

80. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. Immediately after the dose a blood sample is taken and the blood concentration is measured as 200 ng/mL. (200 ug/L) (a)What is the apparent volume of distrib? Conc = Dose / Volume Volume = Dose / Conc = Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

81. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. Immediately after the dose a blood sample is taken and the blood concentration is measured as 200 ng/mL. (200 ug/L) (a)What is the apparent volume of distrib? Conc = Dose / Volume Volume = Dose / Conc = 600 mg / 200.0 ug/L = 600 mg / 0.2 mg/L = 3,000 liters Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

82. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. If, immediately after the dose a blood sample is taken and the plasma concentration is measured as 100 ng/mL. (100 ug/L) (a)What is the apparent volume of distrib? Conc = Dose / Volume Volume = Dose / Conc = Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

83. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. If, immediately after the dose a blood sample is taken and the plasma concentration is measured as 100 ng/mL. (100 ug/L) (a)What is the apparent volume of distrib? Conc = Dose / Volume Volume = Dose / Conc = 600 mg / 100.0 ug/L = 600 mg / 0.1 mg/L = 6,000 liters Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

84. Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. Immediately after the dose a blood sample is taken and the blood concentration Is measured as 200 ng/mL. (a)What is the apparent volume of distrib? (b)What percent of CsA in the body is located in whole blood in this patient? Blood is ~8% of body weight Ms. MJ weighs 55 kg. MJ’s hematocrit is 0.45 (45% cells) Blood Volume=

85. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. Immediately after the dose a blood sample is taken and the blood concentration Is measured as 200 ng/mL. (a)What is the apparent volume of distrib? (b)What percent of CsA in the body is located in whole blood in this patient? Blood is ~8% of body weight Ms. MJ weighs 55 kg. MJ’s hematocrit is 0.45 (45% cells) Blood Volume= 55 kg x 0.08 = 4.4 L Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

86. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. Immediately after the dose a blood sample is taken and the blood concentration Is measured as 200 ng/mL. (b) What percent of CsA in the body is located in whole blood in this patient? Blood Volume= 4.4 L How much is in Blood? = Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

87. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. Immediately after the dose a blood sample is taken and the blood concentration Is measured as 200 ng/mL. (a)What percent of CsA in the body is located in whole blood in this patient? Blood Volume= 4.4 L How much is in Blood? = 4.4 L x 0.2 mg/L = 0.88 mg How much is in the body? Amount in body= Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

88. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Blood sample measures 200 ng/mL. (b) What percent of CsA in the body is located in whole blood in this patient? Blood Volume= 4.4 L How much is in Blood? = 4.4 L x 0.2 mg/L = 0.88 mg How much is in the body? Amount in body= 0.2 mg/L x 3000L = 600 mg (dose) Proportion in whole blood ? Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

89. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Blood sample measures 200 ng/mL. (a)What percent of CsA in the body is located in whole blood in this patient? How much is in Blood? = 0.88 mg How much is in the body? = 600 mg (dose) Proportion in whole blood ? = 0.88 mg / 600 mg = 0.0015 = 0.15% Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

90. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. Immediately after the dose a blood sample is taken and the plasma concentration is measured as 100 ng/mL. (b) What percent of CsA in the body is located in plasma in this patient? Plasma Volume= 4.4 L x 0.55 = 2.42 L How much is in plasma? = Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

91. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Cyclosporin is “highly bound to RBC” and the “Blood : Plasma ratio is 2”. Immediately after the dose a blood sample is taken and the plasma concentration is measured as 100 ng/mL. (a)What percent of CsA in the body is located in plasma in this patient? Plasma Volume= 2.42 L How much is in Plasma? = 2.42 L x 0.1 mg/L = 0.242 mg How much is in the body? Amount in body= Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

92. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Plasma sample measures 100 ng/mL. (b) What percent of CsA in the body is located in whole plasma in this patient? Plasma Volume= 2.42 L How much is in Plasma? = 2.42 L x 0.1 mg/L = 0.242 mg How much is in the body? Amount in body= 0.1 mg/L x 6000L = 600 mg (dose) Proportion in Plasma ? Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

93. Cyclosporin (CsA), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Plasma sample measures 100 ng/mL. (a)What percent of CsA in the body is located in plasma in this patient? How much is in Plasma? = 0.242 mg How much is in the body? = 600 mg (dose) Proportion in plasma ? = 0.242 mg / 600 mg = 0.000403 = 0.0403% Equations Conc = Dose / V V = Dose/Conc A Fifth Example - cyclosporin

94. Comparison Blood : Plasma Concentration(ng/mL)200100 Tissue Volume (L)4.42.42 Amount in Tissue (mg)0.880.242 App Vol. Dist.(L)3,0006,000 Dose (mg)600600 Percent in blood/plasma (%)0.150.04 A Fifth Example - cyclosporin Does the difference in apparent volumes imply anything about where cyclosporin distributes to? If you are told* (published knowledge) that a particular concentration must be achieved in this patient; e.g. 400 ng/mL in whole blood … What volume of distribution would you use? What is your recommended dose? ~ 0.88 mg

95. Comparison Blood : Plasma Concentration(ng/mL)200100 Tissue Volume (L)4.42.42 Amount in Tissue (mg)0.880.242 App Vol. Dist.(L)3,0006,000 Dose (mg)600600 Percent in blood/plasma (%)0.150.04 A Fifth Example - cyclosporin Does the difference in apparent volumes imply anything about where cyclosporin distributes to? If you are told* (published knowledge: ~ MIC, ED, therap range) that a particular concentration must be achieved in this patient; e.g. 400 ng/mL in whole blood … What volume of distribution would you use? (Vol BLOOD ) What is your recommended dose? (1.2 gm) ~ 0.88 mg 50

96. General Principles of Distribution Summary 1.The calculated apparent Volume depends on the fluid being sampled. 2.Drugs can go anywhere (phys.-chem. prop.) leaving extra-cellular water to distribute into bone, fat or … anywhere, any tissue. 3.The apparent Volume depends on the host, and the physical/chemical properties of the drug or metabolite. 4.The calculated apparent Volume rarely reflects a real physiologic volume. 5.The minimum volume* of distribution is vascular volume (8% IBW: 6’ ♂ = 6.4L). 6.There is no maximum volume*.6