One of the most mistunderstood pharmacokinetic (PK) parameters is volume of distribution. First of all it has numerous abbreviations (V, Vd, Vz, Vss, V1, Vc, 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 | 15 |
| Plasma | 7 |
| Whole Body | 42 |
Drugs that have a volume of distribution 7 L or less are thought to be confined to the plasma, or liquid part of the blood. If the volume is between 7 and 15 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.
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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.
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