Almost everyone familiar with pharmaceuticals has heard a conversation like this before:

Scientist 1: “What are the pharmacokinetics of Drug X?”

Scientist 2: “Drug X follows a 1-compartment model in rats, but in monkeys it tends to have a distribution phase and seems to follow 2-compartment kinetics.”

Scientist 1: Thinks to himself/herself …’What does a compartment have to do with this! A compartment is something you find in a train!’

Compartments are an important concept in pharmacokinetics (and pharmacodynamics), but they are rarely explained to other scientists. Hopefully this post will demystify the idea of compartments and show you that the concept of compartments is simple.

To understand compartments, think about your heart for a minute. A human heart has 4 distinct chambers, each with a specific function. Blood, which has been depleted of oxygen returns through the veins to the right atrium. It is then transferred to the right ventricle. The right ventricle pumps the blood into the lungs and then the blood moves into the left atrium. Finally the blood moves into the left ventricle which pushes the blood through the arteries of the body to distribute the oxygenated blood to all of the organs and tissues of the body. Each chamber of the heart has a specific function, and there is a specific flow of blood involved. The following schematic depicts the 4 chambers of the heart along with the direction of blood flow.

As you can see, the blood has unidirectional flow from one chamber to the next. In other words, the blood does not move from the right ventricle back into the right atrium (at least it doesn’t happen with a normal, healthy heart!). If this makes sense to you, then you now understand the idea of compartments. In a very real way, the chambers of the heart are separate “compartments” that the blood passes through.

In pharmacokinetics we don’t use tangible “compartments” like the chambers of the heart. Instead we use theoretical, or imaginary “compartments”. If you were to draw a picture of all the organs and tissues of the body, each as a separate compartment, it would look something like this (image from dougneubauer.com):

Even this model is a bit simplistic for the body, are all muscles the same? What is the “Rest” of the body? Clearly, if we tried to identify every single different tissue in the body, we would have infinite “compartments” in our model. Pharmacokineticists like to simplify things significantly. Thus, instead of defining tangible compartments, we design theoretical compartments with *unique* names like 1, 2, 3, central, peripheral, etc. (I hope you noticed the sarcasm!). Then we draw arrows between these compartments to show how the drug travels from one compartment to the other. Here are 2 examples:

#### 1-Compartment Model

- Drug enters the central compartment (or compartment 1) from somewhere outside of the body.
- Drug then leaves the central compartment. This is analogous to the drug leaving the body.
- Drug recirculation does not occur (output line does not reconnect with input line).
- The 1-compartment model considers the entire body, and all of the organs and tissues to be one giant bucket.

#### 2-Compartment Model

- Drug enters the central compartment (or compartment 1) from somewhere outside of the body.
- Drug then leaves the central compartment by one of two paths:
- the peripheral compartment (also called compartment 2) or
- drug leaves the body

- Drug that is in the peripheral compartment can return to the central compartment.
- Drug recirculation occurs between the central and peripheral compartment, but once drug leaves the body, it does not re-enter the body.
- The 2-compartment model considers the entire body, and all of the organs and tissues to be two buckets, but all drug must leave the body through a single bucket.

In many ways the compartmental models are very similar to the heart chamber model. These models show movement from one “chamber” to another. The 2 key differences are that the pharmacokinetic models are not closed systems (drug is not recirculated from output to input); and pharmacokinetic models permit bi-directional movement (the heart chamber model only allows unidirectional movement).

Hopefully you now understand what is meant by compartmental models in pharmacokinetics. In essence, the number (1, 2, 3) refers to the number of circles drawn on the paper. Many may be asking * why* we use compartment models in pharmacokinetics. The brief answer is that the mathematical functions associated with compartment models seem to describe the observed data very well. It is for practical reasons, not physiologic reasons that we use compartmental models. I will leave the detailed explanation for another blog post.

Hi Dr Nathan,

Thank you for the great explanation on these compartmental model.

May I know what is the difference between non-compartmental and 1-compartmental model?

I am also confused with certain equation such as (I couldn’t find such a thread in this blog)

1. Vd= dose/Co

2. Vd= dose/ Kel*Total AUC

I am not sure which is right to be used for I.P route analysis

Would you please comment on this?

Thanks,

Sophie

Sophie,

Thank you for your comments and questions. I will try to answer them in the order you presented.

1. What is the difference between non-compartmental and 1-compartmental models?

A1. Non-compartmental analysis does not assume any compartmental model. It simply calculates PK parameters from observed data. 1-compartment models are mathematical models that assume that drug distribution follows the characteristics of 1-compartment.

2. Confusion about equations to calculate volume of distribution and which to use for IP route.

Vd = Dose/C0 should only be used for IV doses

Vd = Dose/Kel*Total AUC can be used for any route of administration. This is a combination of 2 equations: CL/V = Kel and CL = Dose/AUC. By rearranging those 2 equations you can get Vd = Dose/Kel*Total AUC.

I hope that helps you!

Nathan

Hellow, Dr Nathan,

Thank you for your good explanation about pharmacokinetics informations.

I have been confused about necessity of noncompartmental analysis.

I think that compartmental analysis is more accurate and reliable than noncompartmental analysis due to reflecting compartments in body.

Also, compartmental analysis colud calculate PK parameters like AUC and Cmax …etc and complicated calculating equation was processed by many program like WinNonlin.

By the way, Why we use noncompartmental analysis for calculating PK parameters?

Could you please reply on this?

Thank you for your teaching in advance.

Best wishes.

Pita.

Hi Pita,

That is a very good questions. There may be many reasons why noncompartmental analysis (NCA) is used instead of compartmental analysis; however, I think the primary reason is time. Noncompartmental analysis can be completed in a matter of minutes while compartmental analysis requires more time. There is another large distinction between the two types of analysis. NCA is purely observational, meaning it has no predictive properties for what might happen in the future. Compartmental analysis is observational and predictive. Thus, if you only need observational reporting, then NCA is often adequate. But if you need predictive capabilities, you have to use compartmental analysis.

Nathan