One of the most misunderstood 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 its 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.

Thank you for your explanation!

I have a question please:

How can we calculate the Volume of Distribution for a new drug?

Best regards.

Volume of distribution can be calculated by running a pharmacokinetic study, collecting blood/plasma samples, measuring drug levels in each sample, and performing either non-compartmental analysis or fitting the concentration-time data to a PK model.

sir

please justify how you have taken volume of distribution of paracetamol is 51L.

Which is neither coming from practical formula of Vd=X/C nor given in literature please justify

Nitish,

Thank you for your question.

Here is a link to one reference that has paracetamol volume of distribution at 65 L (http://sepia.unil.ch/pharmacology/index.php?id=87).

Here is another reference that lists the volume of distribution at 0.9 L/kg (http://link.springer.com/article/10.2165/00003088-198207020-00001).

The value I used was taken from some historical materials that I had and is used for illustrative purposes only. You can change the value to any number you like, but the principle is still the same. Volume of distribution is not a real number that is related to a physical space or volume. It is simply a proportionality constant between the amount of drug in the body and the concentration of drug measured in a body fluid.

Nathan

Thank you for your explanations. Could you please explain us about volume of distribution in tissue as data generated by WINNONLIN in ug/(ng/g)?

Vinod,

I don’t quite understand the question. Perhaps you could expand on your example a bit more.

Dear Dr. Teuscher,

Many thanks for the very interesting article.

Can I say that the volume of distribution indicates the capacity of a drug to “leave” the circulatory system?

Kind regards,

Luiz

Is the volume of distribution measured with or without proteins like albumin?

For the drug acitretin I found the values

protein (albumin) binding 99.9%

volume of distribution 9l/kg, that is 630 l for a man of 70 kg

without albumin I would get a value of more than 4000 l (1000 times the free drug in the blood) – much more than the 630 l;

with albumin I have the situation:

less than 1% of the drug is in the 4l (7l) blood, 99% in the remaining 620+ l

nearly all of the 1% in the blood is bound to albumin (it is not saturated because the amount of albumin molecules within the blood is 50 times the number of drug molecules); 0.001% is free in the plasma;

another 1% of the drug should be bound to albumin within the body; about 0.01% should be free in the body liquid;

The drug has nearly no lipid binding (http://www.actasdermo.org/en/guidelines-for-use-acitretin-in/articulo/S1578219013001479/);

The question remains: Where is the drug, or which values are measured in a wrong way?