Topic 2 - volume of distribution

Apparent volume of distribution Naproxen Vd = 7 L Despiramine Vd = 2800L

-naproxen = has a low volume of distribution = 7 L which means highly plasma bound -high plasma bound = stuck in the circulation -despiramine = psychotic drug, has as high Vd (2800 L), what this means is that most of the drug is in the tissue, need high lipophillicity to pass BBB so makes sense If give 200 mg of both drugs, will get a much higher plasma concentration of naproxen

There are a variety of factors that can influence the extent of plasma protein binding of a given drug by affecting one or more of the basic parameters with define the equilibrium between drug and protein. The two below are the most commonly encountered: 1. Protein concentration 2. Competition 3. Which drugs are more highly protein bound?

1. -a variety of disease states can alter: renal failure, burns, stress/trauma, pregnancy 2. for the # binding sites on protein molecule by concomitant administration of another drug that competes with the drug of interest for protein binding sites -if decrease the plasma bound = increase fu - if have competition, increase fu 3. atenolol, lithium, metformin, ranitidine = no plasma protein binding naproxen = highly plasma protein bound

Apparent Volume of Distribution (Vd) 1. what is it 2. IT IS NOT 3. Is is a PK parameter that attempts to

1. Is the theoretical volume of fluid into which the total drug administered (dose) would have to be diluted to produce the observed plasma concentration. 2. A PARAMETER THAT REFERS TO AN ANATOMICAL OR PHYSIOLOGICAL SPACE 3. -quantitate drug distribution (when Vd is large, then the drug is widely distributed in the body, when Vd is small, the drug is narrowly distributed in the body) -Relate a measured plasma concentration to the amount of drug in the body Notes: vd = measures the extent of distribution -Vd has units of volume (almost always in liters) -relates plasma concentration to amount of drug in the body on Eqn sheet: Vd = amount of drug in the body / plasma concentration

Vd is related to binding in both plasma and tissues according to the following simplified relationship: 1. equation 2. variables 3. point of this equation

1. Vd = Vp + Vt (fu/fuT) 2. - Vd is the total volume of distribution - Vp is the plasma volume in liters ≈ 5 L - VT is the apparent tissue volume in liters ≈ 40 L - fu is the unbound fraction of drug in the plasma - fuT is the unbound fraction of drug in the tissue 3. indicate the direction of change of Vd with a change in plasma protein binding or tissue binding

Relating Vd to Plasma Concentration 1. Vd is used clinically to 2. equation 3. example: According to the prescribing information supplied, Ciprofloxacin has a Vdof 130 L in a normal patient population. Norm Ahl is to be started on ciprofloxacin IV with an initial target plasma concentration of 3.85 mg/L. What dose is required?

1. calculate the dose required to reach an initial (peak) desired plasma concentration for IV Bolus Dosing (assuming a one compartment model). 2. dose = C0 * Vd C0 = initial plasma concentration = plasma concentration at time zero -rearrangement of vd = amount od drug in the body/plasma concentration 3. dose = 3.85 * 130 L = 500 mg dose What if Vd was 65 L? then the dose would be 250 mg If Vd doubles, the dose would be doubled = 1000 mg

Continued scenario: This is analagous to what happens to most drugs when they distribute from the bloodstream into different tissues 1. It appears that 2. this is the

1. in order to account for the resulting blood concentration of drug that the drug has dissolved into a large volume 2. Volume of Distribution (Vd) of a drug Notes: In tank #1 = most of the dye is in water and it has a small relatively speaking volume = most of the drug will be in the plasma so it has a small vd In tank #2 = most of the dye is adsorbed onto the liner, so it has a high volume and so most of the drug is in the tissue and have a high Vd

Vd 1. For the vast majority of drugs 2. The major reason for this statement is that 3. For drugs that are highly tissue-bound, 4. Drugs that remain in the circulation tend to

1. one cannot make any sense of V d or imply a distribution to any specific anatomical space. 2. most drugs bind to tissues throughout the body or distribute into fat. 3. comparatively little of a dose remains in the circulation to be measured; thus, plasma concentration is low and volume of distribution is high. 4. have a low volume of distribution and a high plasma concentration

Vd Relates the Plasma Concentration to the Amount of Drug in the Body 1. Vd is used clinically to 2. Vd = 3. Example: After 5 hours, Norm's plasma levels of ciprofloxacin has declined to 0.95 mg/L. What percent of the original dose remains in his body? Vd = 130 L, original dose = 500 mg

1. relate the amount of drug in the body to the observed plasma concentration, at any time and for any route of administration. 2. Vd = amount of drug in the body/plasma concentration of the drug 3. amount of drug in the body = vd*plasma concentration 130 L * 0.95 mg/L = 123.5 mg %remaining = 123.5 mg/500mg = 0.25 or 25% -which means we have lost 75% =two half lives of the drug

Vd Does Not Relate to an Anatomical Space 1. rather it is a term that 2. To illustrate, let's assume we add exactly 1,000 mg of dye to a large, underground, stainless steel tank filled with water whose volume we want to determine. The tank is mixed well, we obtain a sample of liquid, assay, and determine a dye concentration of 1 mg/L. What is the volume of the tank?? 3. Let us now repeat this experiment with a second stainless steel tank. When we add our dye as above and assay for its concentration, we find it to be 0.01 mg/L. What is the calculated volume of this tank??

1. relates the amount of drug in the body to the concentration of drug in the plasma. It is a term that will inform you as to the distribution of drug in the body: whether the drug is in the plasma or out in the tissue 2. volume tank (L) = amt dye added (mg)/concentration of dye in H2o (mg/L) = 1000mg/(1mg/L) = 1000 L 3. volume tank (L) = 1000 mg / 0.01mg/L = 100,000 L -huge difference

KEY POINTS for Vd: The extent of distribution into tissues (in other words the extent of Vd) depends upon the: 1. Plasma protein binding of the drug 2. Lipid solubility of the drug . 3. Tissue binding of drug .

1. remember from Pharmaceutics II that only free drug can distribute out of plasma. Therefore highly plasma protein - bound drugs have small volumes of distribution. -if a drug is highly plasma bound = small vd 2. the more lipid soluble the drug, the easier it penetrates membrane barriers and adipose tissue. Thus lipid soluble drugs tend to have high Vd 3. drugs that bind to tissue (skeletal muscle, nucleic acids etc.) tend to distribute out of plasma and into tissues. These drugs have high Vd's. Notes: 2 and 3 are looked at the same but they are physicochemically and clinically different but to a PK pharmacist, considered tissue binding bc PK result is the same ex. have a drug that is highly born to skeletal muscle, more muscley patient will have a higher Vd

Fraction Unbound in the Tissue (fUT) 1. fUT represents 2. like plasma protein binding, drug monographs report the fraction bound to the tissue (% bound tissue, or fbT), and like with plasma protein binding you will need to convert this number to the fraction unbound

1. that fraction of drug in the body that is NOT bound to tissue 2. fuT = 1 - fbT

Plasma Protein Binding of Drugs 1. only ____ is able to leave systemic circulation 2. therefore, Vd is directly proportional to 3. total plasma concentration includes both 4. fu = 5. this ratio has a limiting value of 6. the lower the fu, the 7. In most drug monographs, the fraction bound (fb) to plasma proteins is reported. YOU must make the conversion to fu

1. unbound drug 2. fraction unbound of drug in plasma 3. bound and unbound drug 4. fu = Concentration unbound/concentration total 5. 0 to 1 or 0% to 100% 6. more highly protein bound the drug 7. fu = 1 - fb monograph: drug x is y% bound to plasma protein, ex. 99% bound = 1% unbound

Tissue Binding of Drugs (fUT) Drugs bind to many substances other than plasma proteins.

Binding usually occurs when a drug associateswith a macromolecule intissuebut may occur when a drug is partitioned into body fat (highly lipid soluble drugs). Some drugs accumulate within cells because they bind with proteins, phospholipids, or nucleic acids. For example, chloroquine (concentrations in tissue can be thousands of times higher than those in plasma) binds to anionic sites in many tissues.

Ex. Consider the following table, based upon a "normal" 70 kg male: So if a drug molecule distributed exclusively into total body water it would have a volume of distribution (Vd) of about 30-50 L. If it distributed exclusively into blood, it would have a Vdof about 3-5 L. Problem: Chloroquine (antimalarial) has a Vd of 13,000 L It is obvious that the Vdof chloroquine cannot be a real space, but is rather an apparent space relative to the plasma concentration of the drug.

Notes: these are fluid volumes, total body water volume = 30-50 L -Chloroquine has a Vd of 13000 L which means 1 L of water = 1 kg, so 13,000 L = 13,000 kg = 28k lbs -what this means is that if you give this drug to a patient= so little of it is found in the patient's plasma that it looks like they have this huge volume -this means most of it is in the tissue **DO NOT MEMORIZE VALUES, WILL BE ON EQN SHEET Vplasma = 5 L Vtissue = 40 L

Continued scenario: What if I told you the two tanks were exactly the same size?

Tank #1 = typically stainless steel tank, all of the dye added is in the water phase Tank #2 = has a charcoal liner which absorbs most of the dye -very little is in the water which is why the volume looks so big, not so much because its a bigger tank, but tank #2 is all in the charcoal liner

Vd is a primary PK parameter •It is an indication of the extent of distribution of the drug within the body •It is determined by the physicochemical properties of the drug and the physiological parameters of the patient •It depends on binding to both plasma proteins and tissue constituents

fu/fuT = physicochemistry of the drug and the physiology of the patient

plot of the Vd of propranolol as a function of fu (in the plasma)

y= Vd, x= fu (independent variable) -Vd increases as fu increases, therefore vd is proportional to fu