One of the most mistunderstood pharmacokinetic (PK) parameters is volume of distribution. First of all it has numerous abbreviations (V, V_{d}, V_{z}, V_{ss}, V1, V_{c}, V2, etc.), and to make matters worse, many people incorrectly define the parameter. But, once you understand the meaning behind volume of distribution, you will have a solid grasp on the fundamentals of pharmacokinetics.

Let’s start with the basic definition of volume of distribution. The volume of distribution is a proportionality factor that relates the amount of drug in the body to the concentration of drug measured in a biological fluid. That’s it … a proportionality factor … nothing more. You can stump your professor, mentor, or other pharmacokinetic scientists with this little definition.

The power behind understanding volume of distribution comes from the explanation. Think about taking a 500 mg tablet that contains acetaminophen (Tylenol^{®} or paracetamol for those European readers). You have just placed 500 mg of drug in your body, or mathematically:

Amount = 500 mg

Now imagine having a blood sample drawn from your vein about 1 hour later. From that blood sample, we measure the concentration of drug in the plasma (blood = plasma + red blood cells), and it is ~~16~~ 8 μg/mL, or mathematically:

Concentration = 8 μg/mL = 0.008 mg/mL = 8 mg/L

Now, let’s ask a simple question: how much drug is in the body? We know what the concentration of drug is in the plasma, but we cannot convert that to a total amount without knowing the volume of the human container. In the case of acetaminophen, the volume of distribution is about 51 L. Now, you can multiply the concentration times the volume of distribution to arrive at the amount of drug in the body at 1 hour post dose:

Amount (1 hour post dose) = 8 mg/L * 51 L = 408 mg

Now we can compare the amount remaining in the body (408 mg) with the amount of drug administered (500 mg). As you can see volume of distribution is just a proportionality factor that helps convert between amounts and concentrations.

Volume of distribution is called a “primary pharmacokinetic parameter”, which means that this parameter depends on the *physiologic properties of the body* and the *physiochemical properties of the drug*. Volume of distribution is not derived from other PK parameters, instead it is used to estimate the “secondary” PK parameters.

This concept is similar to the primary and secondary colors. Primary colors are RED, YELLOW, and BLUE. These colors are the source for all other colors. Secondary colors are 50/50 mixtures of 2 primary colors, and they are ORANGE (RED + YELLOW), GREEN (YELLOW + BLUE), and PURPLE (BLUE + RED) [Image by Leopard Print]. Much in the same way, combining 2 primary PK parameters will give you a secondary PK parameter. I will give examples of this in a future post, but for now, remember that volume of distribution is primary PK parameter.

But what about all of those different terms? Well, each of the different volume of distribution parameters refer to either volumes associated with different theoretical compartments or different methods of calculating the volume of distribution. There is no consensus on which one is “right”, because each method has it’s advantages and shortcomings. Future posts will describe the details of each of these versions of the parameter.

At the beginning of this post, I indicated that understanding the definition of volume of distribution would provide significant insight into pharmacokinetics. Now that you understand the the volume of distribution is a proportionality factor, and not a physiologic value, I can explain why this is important. First, there are a few details on the human body that are necessary for this discussion; the human body is primarily (~70%) water, therefore we can think of the body as containers with water:

Body fluid/structure | Actual volume (L) |
---|---|

Blood | |

Plasma | |

Whole Body | 42 |

Drugs that have a volume of distribution ~~7~~ 4 L or less are thought to be confined to the plasma, or liquid part of the blood. If the volume is between ~~7~~ 4 and ~~15~~ 7 L, the drug is thought to be distributed throughout the blood (plasma and red blood cells). If the volume of distribution is larger than 42, the drug is thought to be distributed to all tissues in the body, especially the fatty tissue. Some drugs have volume of distribution values greater than 10,000 L! This means that most of the drug is in the tissue, and very little is in the plasma circulating. The larger the volume of distribution, the more likely that the drug is found in the tissues of the body. The smaller the volume of distribution, the more likely that the drug is confined to the circulatory system.

I hope that helps you understand volume of distribution. It is a critical PK parameter upon which other concepts will be built. Don’t forget, volume of distribution is just a proportionality factor to relate the amount of drug to the measured concentration.

so, how is the volume of distribution calculated? in an example you mentioned that acetaminophen has a V of 51L. where does this come from and does it vary from individual to individual?

thanks.

Good questions. Volume of distribution is estimated as a parameter from a model fit of the data, or calculated in a noncompartmental analysis. As I noted, volume is a proportionality factor between the concentration measured and the amount of drug in the body. Thus, volume varies across individuals based on their physiologic makeup.

so does changing the dose change the volume of distribution ,for the same individual ?

In most cases, the volume of distribution does not change with dose. However it is possible that distribution is dose-dependent.

You said that some drugs have Vd greater than 10000L……..and they are mostly distributed in the tissues…….

suppose they are almost completely distributed in the tissues but even then how can they occupy 10000L????

Thank you for the question. You are correct that a human being does not have a volume of 10000 L!

The Volume of Distribution is not a physical volume, instead it is a proportionality factor between the amount of drug in the body and the concentration measured in the circulatory system. Drugs that reside primarily in the tissue will have small concentrations in the plasma. Imagine giving a dose of 100 mg (100,000,000 ng) and only measuring 10 ng/mL in the plasma. Also, lets assume 100% bioavailability. Given that Concentration = Amount / Volume, you can calculate the volume of distribution as 100000000 / 10 = 10,000 L.

The key is remembering that the Volume of Distribution is a proportionality factor, not a physical volume.

Hi,

Regarding the example above, does the total amount of drug include free drug molecules and drug molecules that are bound to plasma proteins etc?

Thanks.

These examples are based on the total amount of drug in biological fluid.

Nathan

drug with high Vd are distributed to tissues only small amount reaches plasma…? then what happens to the drug in tissues ? is it slowly released in plasma after the plasma drug being excreted out ? or drug remains in tissue for so long ?

Your interpretation is correct. Drug molecules are constantly moving between tissues and the plasma. As a drug molecule is eliminated from the plasma, the drug molecules in the tissue move to replace it. Since movement from tissue to plasma slower than clearance from the plasma, this distribution process becomes the rate limiting step. Eventually all of the drug molecules leave the tissue and are cleared from the body.

Thank YOu very much Mr. Nathan… thats very easy explanation i had to present on TDM to Physicians and your this post helped me alot… just have to ask can i ask u question when i feel stuck somewhere in PK of drugs

I’m happy to help! You are welcome to ask questions anytime. You can post on my blog, or use the contact menu at the top of the page.

please Mr Nathen how dose Vd change with disease

Nabeil,

Thank you for the question. Changes in the volume of distribution may occur with different diseases, but I haven’t found a lot of research on the topic. There is one publication from 1976 on the topic that you may want to review (Klotz U., Pathophysiological and disease-induced changes in drug distribution volume: pharmacokinetic implications. Clin Pharmacokinet. 1976;1(3):204-18.). The change in volume of distribution depends on the type of disease and how that disease affects the physiology of the individual.

Dear Nathan,

I have a few questions:

1) I might be missing something but the actual volume of blood in the body should be about 5.5 liter (male). How come that in your table it is 15?

2) Is it possible that Vd<Volume of plasma (drug conc measured in plasma)

3) Imagine that you work w poorly absorbed drug w absolute BA of c.a. 1%. So you administer it orally and measure a tiny fraction of it in the plasma. Will your PK model show a big Vd value because it thinks that all the drug sits in the tissues but instead 99% is excreted w feces?

Thank you in advance!

Basil, Thank you for your questions. Here are brief responses:

1. Total blood volume includes plasma as well as the cellular components of blood. It has been estimated that total blood volume is about 15 L.

2. It is possible that Vd is less than plasma volume. Remember, that volume of distribution is simply a proportionality factor between measured concentrations and amount of drug in the body. While this situation is rare, it is possible.

3. As I mentioned in answer #2, Vd is a proportionality factor. If you don’t know the absolute bioavailability of a drug, then you cannot calculate Vd, you can only calculate Vd/F. However, if you know the absolute bioavailability, then you are calculating the actual proportionality factor between the amount of drug and concentration of drug in the body. This number is unaffected by the bioavailability, therefore it would be incorrect to say that Vd is large because of low bioavailability. If on the other hand, you don’t know the absolute bioavailability of your compound, then large values of Vd/F could be due to low bioavailability or wide tissue distribution.

I hope that helps.

-Nathan

Till now I do not understand what is the difference between Vd and apparent Vd ?? ,,, and is it right that vd = dose \ concentration of drug in blood

Vd is the volume of distribution which is a proportionality factor between the amount of drug in the body and the concentration measured in blood/plasma/serum. Apparent Vd is Vd/F, or volume of distribution adjusted for bioavailability. Following oral administration, unless you know the absolute bioavailability, you cannot determine the actual volume of distribution. Many drugs are not able to be administered intravenously, making it very difficult to determine the absolute bioavailability. Therefore many reports will list the “apparent Vd” or Vd/F.

thank you,very educative

if volume of distribution if proportionality factor then factor should not change from one person to another. it should stay constant. And you are saying “volume varies across individuals based on their physiologic makeup.”

Please Explain

Ashok,

Thank you for your comment. I believe both statements to be accurate, but I can see the confusion that it might cause. Volume of distribution is a mathematical term that represents the relationship between the amount of drug in the body and the concentration measured in the blood or plasma. Another similar term is “lung capacity” or amount of air that can be held in the lungs. Both of these are mathematical terms; however, they are impacted by changes in physiology. With respect to lung capacity, individual people may have different capacities based on body size, gender, race, and disease status. And individuals may have changing lung capacity if key factors change (e.g., body weight, smoking activities, tumor growth, etc.). Thus lung capacity can change within an individual person, and it is different across different people. The volume of distribution is similar, but the factors are different (e.g., % body fat, body weight, gender, drug permeability, etc.). Thus, individuals may have changing volume of distribution if their factors change, and different individuals will have different volume of distribution values.

Hopefully that helps you differentiate between a proportionality factor, and a mathematical constant (unchanging value).

Best regards,

Nathan

Thanks Nathan

Dear nathan, As you mentioned, Vd= Dose amount/ concentration in blood. But the concentration in blood is lower and lower with the time pasted. How to understand this?

Qiangang,

The equation used, is based on the initial drug concentration in blood at time=0, or the theoretical maximum. Because Vd is a ratio, the true equation is Vd = amount of drug in the body/concentration of drug in the blood. Unfortunately it is very difficult to know the amount of drug in the body after dose administration because of the elimination processes which remove drug from the body.

Nathan

Hi,

I understood the VD of APAP to be ~ 1L/Kg, or 0.95 L/kg. In the example the VD is 51, so the patient is around 118 lbs give or take. If you took a 70kg person, with a larger VD, and given the same example, a measured concentration of 8 mg/L, the calculated amount is in excess of the administered dose. What am I missing? Thanks

Thanks for the question. As you indicate, a larger person would have a larger Vd (~67 L for a 70 kg person). With a larger Vd, the concentration measured in the plasma will be lower since the concentration is equal to the amount divided by the volume (C = A/V). Thus, if there was 408 mg of drug in the body, the measured concentration would be 6 mg/L. You are correct that it would be unlikely to measure 8 mg/L in a larger individual.

Thanks for the question.

I don’t understand how you determined blood volume and plasma volume. My understanding is that normal plasma volume is 0.04L/kg and blood volume 0.07L/kg. These values are 50% less than you describe. How do you explain this?

Thank you for your comment. The post has been updated with more accurate estimates of plasma and blood volumes.

why volume of distribution is greater in renal failure and hepatic failure .

Amita,

In renal failure, patients retain water because they cannot excrete salts and fluids through the kindeys. The increased amount of water in the body can increase the volume of distribution for hydrophilic drugs.

In hepatic failure, plasma protein production decreases which also leads to fluid retention. The increased fluid in the body can increase the volume of distribution for hydrophilic drugs.

Nathan

how it is related with loading dose..?

Hi Amita,

I’m not sure I understand your question. Volume of distribution is an independent pharmacokinetic parameter that depends on the physiology of the body and the properties of the drug molecule.

Nathan

I’m trying to understand how medication dosing might change after one has a gastric bypass procedure. If one takes a drug with a large Vd, meaning the drug distributes into adipose tissue, and then loses 100 pounds of fat after bariatric surgery, how does this affect the dose?

Would this be the same with a small Vd drug since after surgery there would then be less total body fluid for distribution?

Thank you so much!

Katharine,

Excellent question. Significant physiological changes may impact the pharmacokinetics and pharmacodynamics of drugs. Before answering your question, let’s consider 2 separate situations. The first is a drug with a very large volume of distribution, but that the Vd for each patient is about the same, regardless of weight. The second drug has a large volume of distribution, however, Vd is proportional to body weight, which means as weight increases, so does Vd.

Now to answer your question. For Drug 1, a large change in weight is unlikely to affect the Vd because the drug distributes to all tissues in the body, not just fat tissue. For Drug 2, a large change in body weight would affect Vd, and you would likely decrease the administered dose.

So, you to address the problem for a specific drug, you will need to know the volume of distribution AND the relationship of that parameter to body weight.

Thanks for the question!

Nathan

What are the characteristics of a drug that determines the Volume of Distribution? For example, does a hydrophilic drug have a low Vd, while a lipophilic drug will have a high Vd? What other aspects of the drug molecule determines the Vd?

Mary,

There isn’t a set list of molecular characteristics that determine the Vd for a drug. In general, you are correct that hydrophilic drugs tend to have low volume of distribution and lipophilic drugs have a high volume of distribution. But the specific Vd for a molecule cannot be predicted (in my opinion) from pysiochemical properties alone. The Vd is a proportionality factor between the amount of drug in the body and the concentration of drug measured in some fluid in the body. Thus Vd can be different for each fluid that is measured. Additional aspects that can affect Vd are transporter systems, tissue binding, and sequestration of the drug. Ultimately the best way to determine Vd is to measure the concentration-time profile.

Nathan

Hi! I think it was a good description but i am confused over one thing.

How can you determine the volume of distribution for certain drugs? For example drugs with a volume of distribution of 10 000, that means that they have been distributed to the tissues to a large extent. But isn’t the concentration of the drug in the plasma the only thing that we can measure? So based on the concentration of the drugs concentration in plasma, how is it possible to know if it has been distributed to the tissues or not? (With the volume of distribution of course, but i dont understand how it is possible to found such a value for different drugs).

Thanks in advance!

Best regards

Alexander

Alexander,

Thanks for the question. Volume of distribution is simply a proportionality factor relating the amount of drug in the body to the concentration you measure in a biological fluid (e.g., plasma). As you correctly state, you cannot be certain that a drug enters tissues unless you measure it in those tissues. The volume of distribution makes the assumption that the drug distributes evenly and instantaneously through the body. By measuring the concentration in one location, we assume that the same concentration occurs throughout the body. Using those assumptions and the single measurement, we can calculate a theoretical volume. Again, this is simply a proportionality factor to help us with calculations that relate dose to concentration.

Nathan

Thank you for this great explanation, Nathan.

I want to ask about the difference between Distribution and Volume of Distribution. For instance, Vancomycin is widely distributed in most tissues and fluids (except poor CSF and lung penetration). But it is also my understanding that Vancomycin has a small Volume of Distribution due to its hydrophilicity, i.e. it likes to be in body fluids and not fatty tissues.

I believe the same could be said of the Aminoglycosides. Gentamicin is widely distributed, but has a small Volume of Distribution.

So it seems that widely distributed drugs have a small Volume of Distribution? Am I missing something?

Thank you very much for your help with this!

Michael

Michael,

Thank you for your question. It can be very confusing when the same word is used multiple times for different things. The PK parameter “Volume of Distribution” is a proportionality factor that relates the amount of drug in the body to the concentration measured in some biological fluid. It is simply a math term that helps us with our equations. The “distribution” of a drug generally refers to either the process or extent to which a specific drug molecule moves through tissues in the body. Thus, you can have a drug the “distributes” to a specific organ, yet has a small volume of distribution. This is common with agents that might take advantage of some targeting moiety.

With respect to Vancomycin, it has a volume of distribution of approximately 0.7 L/kg (or 49 L for a 70 kg person). That is larger than total body water (42 L), which means that it distributes to more than just the total body water. It gets into the tissues. The volume of distribution for Vancomycin is not considered small, although it is much less than some other drugs (e.g., Digoxin has a Vd of 500 L). I believe a “small volume of distribution” would be less than 15 L (<0.2 L/kg). Anything larger than 42 L (>0.6 L/kg) would be considered large. Thus, aminoglycosides would fall into the moderate to large volume of distribution category for me … which is consistent with their distribution to most of the tissues of the body.

I hope that helps!

Nathan