Distribution From A Physiologic Perspective Objectives Problems Questions

Distribution From A Physiologic Perspective Objectives • 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.

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?

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

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

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

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 Plasma or Serum ~ 55% RBC’s, ~ 45% of whole blood Extra-cellular Water ~ 15 L Intra-cellular Water ~ 25 L Whole Blood ~ 5 L

Body Water 1 Tissue Skin Muscle Brain Skelton Adipose Other Total 1. % Water 72 75 75 22 10 %Weight 18 42 2 16 ~10 12 100 Skelton, H. Arch Int. Med 1927; 40: 140. Water per 70 kg (L) 9. 1 22. 1 1. 1 2. 5 0. 7 6. 5 42

General Principles of Distribution 1000 mg 10 L 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/ 10 L = 100 mg/L C = Amount / volume Volume = Amount / C

General Principles of Distribution 1000 mg 10 L If you add 1000 mg of a drug to 10 L of water, what is the final concentration? C = Amount / volume Volume = Amount / C Could the concentration change as a function of time after addition? 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?

General Principles of Distribution 10 L Charcoal Again you add 1000 mg of a drug 1000 mg 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 = 20 L …? ? ? BUT The real volume is 10 L

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

General Principles of Distribution Again you add 1000 mg of a drug 1000 mg but this time in addition to the charcoal and 10 L of water there is 1 L of oil. 1 L You measure the concentration in the oil (150 mg/L) and in the water (25 mg/L). 10 L Now calculate the volume: Charcoal 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

General Principles of Distribution Mass Balance 1000 mg 1 L Water: Concentration 25 mg/L True Volume: 10 L Amount of Drug = 250 mg Apparent Volume = 40 L 10 L Oil: Charcoal Concentration 150 mg/L True Volume: 1 L Amount of Drug = 150 mg Apparent Volume = 6. 66 L Charcoal: (therefore) Amount = 600 mg

General Principles of Distribution 1000 mg Conclusions 1 L 10 L Charcoal 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 1000 mg…so what is the Apparent Volume of Distribution? 1 L 10 L Charcoal … 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 …so, if it is not real, how useful is it? 1000 mg Uses: 1 L • 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. 10 L Charcoal

General Principles of Distribution L/70 kg 50, 000 20, 000 10, 000 5, 000 1, 000 500 100 50 10 5 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

General Principles of Distribution Question: If the drug is distributing to total body water, why are there large differences in the volume for different drugs? 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

General Principles of Distribution 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 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 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 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 <effectively> 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 Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can The volume of distribution distribute to tissues. 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 (~10 L – e. g. warfarin).

General Principles of Distribution 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 Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. Vd. TOTAL = VB + VT (f. B/f. T) Where VB is blood volume ~ 5 L and VT is body water (between 30 -50 L). f. B and f. T is the fraction unbound in tissue and in blood 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 Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. Vd. TOTAL = VB + VT (f. B/f. T) Where VB is blood volume ~ 5 L and VT is body water (between 30 -50 L). The volume of distribution of a drug can be viewed as a relationship between If f. B is 5% (free in blood or plasma) tissue binding and f. T is 100% binding to protein (free in issues – no binding) within the blood. The final volume is 5 L of blood volume plus ~2. 5 L of tissue volume. 7. 5 L total.

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

General Principles of Distribution Effect of Protein Binding on Volume of Distribution Vd. TOTAL = VB + VT (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.

General Principles of Distribution 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 L/70 kg 50, 000 20, 000 10, 000 5, 000 1, 000 500 100 50 10 5 Quinacrine Chloroquine Nortriptyline Digoxin Five Examples: Example 5: Example 2: Example 1: Example 4: Example 3: Propranolol Quinidine Quinolones (1 - 2 L/kg), Tetracycline Phenobarbital Phenytoin Theophylline (0. 45 L/kg) Aminoglycodises (0. 25 L/kg) ASA Warfarin Cyclosporin … 3000 L Ciprofloxacin … 120 L Levofloxacin … 100 L Levofloxacin … 83. 3 L Theophylline … 36 L Notice that the Volume of distribution is different for all drugs and will also be different for each patient (levo).

Male Acute Community Acquired Pneumonia Distribution Problems Five Examples: Example 1: Levofloxacin Calculate Volume Example 2: Example 3: Example 4: Example 5: Ciprofloxacin Given Volume, Calculate Concentration Theophylline Calculate Volume …then predict new dose Levofloxacin Cyclosporin

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. 4 L). 6. There is no maximum volume*.

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

Male Acute Community Acquired Pneumonia 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/m. L (mg/L) Additional Information: Blood Volume: 8% of body weight Hematocrit: 0. 45

Male Acute Community Acquired Pneumonia 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/m. L (a) how much drug is in the serum? (b) what is the total amount of drug in your patient (MAC)?

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 1 Answers. 1. What is the Volume of distribution of levo? Dose = Initial [ ] = Levo Volume: = 2. Proportion in Serum: =

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 1 Answers. 1. What is the Volume of distribution of levo? Dose = 500 mg Initial [ ] = 5 g/m. L (mg/L) Levo Volume: = Dose / Conc = 500 / 5 = 100 L 2. Proportion in Serum: =

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc 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: =

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc 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: = 0. 08 x 80 kg = 6. 4 L =6. 4 x 0. 55 = 3. 5 L = 500 mg/ 5 mg/L = 100 L Proportion in Serum: =

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc 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: = 0. 8 x 80 kg = 6. 4 L =6. 4 x 0. 55 = 3. 5 L = 500 mg/ 5 mg/L = 100 L Proportion in Serum: = 3. 5 L/100. 0 L = 3. 5%

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 1 Answers. 3. If the serum levofloxacin concentration is at the mid-point of target … ~ 3 mg/L … (a) how much drug is in the serum? (b) what is the total amount of drug in MAC? Therapeutic Range: 5 - 1 g/m. L = mg/L mid point: 3 mg/L Amount in body at equilibrium: = Amount in serum: =

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 1 Answers. 3. If the serum levofloxacin concentration is at the mid-point of target … ~ 3 mg/L … (a) how much drug is in the serum? (b) what is the total amount of drug in MAC? Therapeutic Range: 5 - 1 g/m. L = 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%

Levofloxacin Distribution Problem 1 Review Answers. Volume 100 L/80 kg = 1. 2 L/kg Recall Levo monograph indicated volume was between 74 & 112 L. Body Weight: Blood Volume: 80 kg 8% of body weight Serum is 55% of Blood Serum = (0. 08) x (0. 55) x (80) = 3. 52 L = 3 g/m. L = 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 Serum conc. Percent in Serum: 10. 5 mg / 300 mg = 3. 5%

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

Male Acute Community Acquired Pneumonia 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/m. L (target) Additional Information: Cipro Volume: 1. 5 L/kg Blood Volume: 8% of body weight Hematocrit: 0. 45

Male Acute Community Acquired Pneumonia Distribution Problem 2 Questions 1. What dose should be given to MAC to achieve a peak concentration of between 3 and 4 g/m. L? 2. What percent is located in the Serum? 3. If the serum cipro concentration is at the mid-point of target… 3. 5 g/m. L (a) how much drug is in the serum? (b) what is the total amount of drug in MAC?

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 2 Answers. 1. What dose should be given to MAC to achieve a peak concentration of between 3 and 4 g/m. L? Cipro Volume: Pt weight: 6. 4 x 0. 55 = 3. 5 L Cipro Volume (L): 1. 5 L/kg 80 kg =

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 2 Answers. 1. What dose should be given to MAC to achieve a peak concentration of between 3 and 4 g/m. L ? Cipro Volume: Pt weight: 6. 4 x 0. 55 = 3. 5 L Cipro Volume (L): 1. 5 L/kg 80 kg = 1. 5 L/kg x 80 kg = 120. 0 L Peak target [ ] mg/L = 3 g/m. L Req. Cipro Dose =

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 2 Answers. 1. What dose should be given to MAC to achieve a peak concentration of between 3 and 4 g/m. L? Cipro Volume: Pt weight: 6. 4 x 0. 55 = 3. 5 L Cipro Volume (L): 1. 5 L/kg 80 kg = 1. 5 L/kg x 80 kg = 120. 0 L Peak target [ ] mg/L = 3 g/m. L (mg/L) Req. Cipro Dose = 3 mg/L x 120 L = 360 mg

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 2 Answers. 1. What dose should be given to MAC to achieve a peak concentration of between 3 and 4 g/m. L? Cipro Volume: Pt weight: 6. 4 x 0. 55 = 3. 5 L Cipro Volume (L): 1. 5 L/kg 80 kg = 1. 5 L/kg x 80 kg = 120. 0 L Peak target [ ] mg/L = 4 g/m. L (mg/L) Req. Cipro Dose = 4 mg/L x 120 L = 480 mg

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 2 Answers. 1. What dose should be given to MAC to achieve a peak concentration of between 3 and 4 g/m. L? Peak target 3 mg/L = Dose = 360 mg Peak target 4 mg/L = Dose = 480 mg Common dose of Cipro IV?

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Distribution Problem 2 Answers. 1. What dose should be given to MAC to achieve a peak concentration of between 3 and 4 g/m. L? Peak target 3 mg/L = Dose = 360 mg Peak target 4 mg/L = Dose = 480 mg Common dose of Cipro IV? 400 mg

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc 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: Serum vol. (55%): Cipro Volume: 0. 8 x 80 kg = 6. 4 L 6. 4 x 0. 55 = 3. 5 L 1. 75 L/kg x 80 kg 140. 0 L Proportion in Serum: 3. 5 L/140. 0 L = 2. 5%

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc 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: Serum vol. (55%): Cipro Volume: 0. 08 x 80 kg = 6. 4 L 6. 4 x 0. 55 = 3. 5 L 1. 5 L/kg x 80 kg 120. 0 L Proportion in Serum: 3. 5 L/120. 0 L = 2. 9%

Ciprofloxacin Distribution Problem 2 Review Answers. Body Weight: Blood Volume: 80 kg 8% of body weight Serum is 55% of Blood Serum = (0. 08) x (0. 55) x (80) = 3. 52 L Volume 1. 5 L/kg 120. 0 L = 3 g/m. L = 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) Serum conc. Percent in Serum: 10. 5 mg / 360 mg = 2. 9%

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

Severe Asthmatic Male Distribution Problem 3 Male Asthmatic Age: 45 yr Weight: 80 kg Drug: Theophylline Goal: Serum theophylline in therapeutic range 10 – 20 g/m. L Additional Information: Initial Theophylline Dose of 300 mg produces a peak following a bolus iv dose of 8. 33 mg/L.

Severe Asthmatic Male 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?

Severe Asthmatic Male Equations Conc = Dose / V V = Dose/Conc 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: =

Severe Asthmatic Male Equations Conc = Dose / V V = Dose/Conc 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

Severe Asthmatic Male Equations Conc = Dose / V V = Dose/Conc 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%

Severe Asthmatic Male Equations Conc = Dose / V V = Dose/Conc 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%

Severe Asthmatic Male Equations Conc = Dose / V V = Dose/Conc 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/m. L = 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

Severe Asthmatic Male Equations Conc = Dose / V V = Dose/Conc 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/m. L = 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

Severe Asthmatic Male Equations Conc = Dose / V V = Dose/Conc 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

Distribution Problem 3 Answers. Body Weight: Blood Volume: 80 kg 8% of body weight Serum is 55% of Blood Serum = (0. 08) x (0. 55) x (80) = 3. 52 L Volume 0. 45 L/kg 36. 0 L = 15 g/m. L = 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 Serum conc. Percent in Serum: 52. 5 mg / 540 mg = 9. 8%

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

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”?

Distribution Question Example 4 Equations Conc = Dose / V V = Dose/Conc 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 = Dose / Conc = 500 mg / 6. 0 mg/L =

Distribution Question Example 4 Equations Conc = Dose / V V = Dose/Conc 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 = Dose / Conc = 500 mg / 6. 0 mg/L = 83. 33 liters Notice that this volume is slightly different than the 100 L calculated for a different patient Expressed per kg of body weight =

Distribution Question Example 4 Equations Conc = Dose / V V = Dose/Conc 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 = 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

Distribution Question Example 4 Equations Conc = Dose / V V = Dose/Conc 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.

Distribution Question Example 4 Equations Mr. JR, receives 500 mg and the initial plasma concentration is measured as 6. 0 mg/L. Conc = Dose / V 2. What percent of the drug is in plasma? V = Dose/Conc Plasma volume = 6. 4 L x 0. 55 = 3. 52 L. Conc in plasma = 6. 0 mg/L Amount in plasma =

Distribution Question Example 4 Equations Conc = Dose / V V = Dose/Conc 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 =

Distribution Question Example 4 Equations Conc = Dose / V V = Dose/Conc 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. 33 L = 500 mg (dose)

Distribution Question Example 4 Equations Conc = Dose / V V = Dose/Conc 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. 33 L = 500 mg (dose) Proportion in plasma ? =

Distribution Question Example 4 Equations Conc = Dose / V V = Dose/Conc 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. 33 L = 500 mg (dose) Proportion in plasma = 21. 12 mg / 500 mg = 0. 042 = 4. 2%

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

A Fifth Example - cyclosporin Cyclosporin (Cs. A), 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/m. L. (a) What is the apparent volume of distrib? (b) What percent of Cs. A in the body is located in blood / plasma in this patient?

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (200 ug/L) (a) What is the apparent volume of distrib? Conc = Dose / Volume = Dose / Conc =

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (200 ug/L) (a) What is the apparent volume of distrib? Conc = Dose / Volume = Dose / Conc = 600 mg / 200. 0 ug/L = 600 mg / 0. 2 mg/L = 3, 000 liters

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (100 ug/L) (a) What is the apparent volume of distrib? Conc = Dose / Volume = Dose / Conc =

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (100 ug/L) (a) What is the apparent volume of distrib? Conc = Dose / Volume = Dose / Conc = 600 mg / 100. 0 ug/L = 600 mg / 0. 1 mg/L = 6, 000 liters

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (a) What is the apparent volume of distrib? (b) What percent of Cs. A 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 =

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (a) What is the apparent volume of distrib? (b) What percent of Cs. A 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

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (b) What percent of Cs. A in the body is located in whole blood in this patient? Blood Volume = 4. 4 L How much is in Blood? =

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (a) What percent of Cs. A 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 =

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Blood sample measures 200 ng/m. L. (b) What percent of Cs. A 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 3000 L = 600 mg (dose) Proportion in whole blood ?

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Blood sample measures 200 ng/m. L. (a) What percent of Cs. A 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%

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (b) What percent of Cs. A 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? =

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 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/m. L. (a) What percent of Cs. A 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 =

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Plasma sample measures 100 ng/m. L. (b) What percent of Cs. A 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 6000 L = 600 mg (dose) Proportion in Plasma ?

A Fifth Example - cyclosporin Equations Conc = Dose / V V = Dose/Conc Cyclosporin (Cs. A), 600 mg is administered to a female transplant patient – MJ, who weighs 55 kg, by IV bolus. Plasma sample measures 100 ng/m. L. (a) What percent of Cs. A 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%

~ 0. 88 mg A Fifth Example - cyclosporin Comparison Concentration (ng/m. L) Tissue Volume (L) Amount in Tissue (mg) App Vol. Dist. (L) Dose (mg) Percent in blood/plasma (%) Blood : Plasma 200 4. 4 0. 88 3, 000 600 0. 15 100 2. 42 0. 242 6, 000 600 0. 04 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/m. L in whole blood … What volume of distribution would you use? What is your recommended dose?

~ 0. 88 mg A Fifth Example - cyclosporin Comparison Concentration (ng/m. L) Tissue Volume (L) Amount in Tissue (mg) App Vol. Dist. (L) Dose (mg) Percent in blood/plasma (%) Blood : Plasma 200 4. 4 0. 88 3, 000 600 0. 15 100 2. 42 0. 242 6, 000 600 0. 04 Does the difference in apparent volumes imply anything about where cyclosporin distributes to? If you are told*(published knowledge: ~ MIC, ED 50, therap range) that a particular concentration must be achieved in this patient; e. g. 400 ng/m. L in whole blood … What volume of distribution would you use? (Vol. BLOOD) What is your recommended dose? (1. 2 gm)

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. 4 L). 6. There is no maximum volume*. 6