Lecture 1.5: Compartmental models

Summary

This script discusses the fundamentals of pharmacokinetics, focusing on compartmental models used to describe plasma drug concentration-time data. It compares the simple one-compartment model, where the drug is rapidly and homogeneously distributed, with the more complex two-compartment model, where the drug distributes in two phases: rapidly to the central compartment and more slowly to peripheral tissues. The concept of volume of distribution (Vd) is introduced, explaining how it reflects drug distribution across the body. Challenges in calculating Vd are also addressed, particularly in relation to drug elimination and the need for back-extrapolation of concentration data.

Takeaways

• 😀 A one-compartment model describes a drug administered intravenously, rapidly and homogeneously distributing throughout the body.
• 😀 The two-compartment model is more complex, with the drug first distributing rapidly to the central compartment (blood and well-perfused organs) before moving slowly to the peripheral compartment (poorly perfused tissues).
• 😀 Plasma drug concentration data can suggest whether a drug's pharmacokinetics follow a one-compartment or two-compartment model.
• 😀 In a one-compartment model, drug concentration declines exponentially over time as the drug is rapidly distributed and eliminated.
• 😀 In a two-compartment model, the concentration-time profile shows a faster decline followed by a slower phase after the drug distributes throughout the body.
• 😀 The volume of distribution (Vd) quantifies how extensively a drug distributes throughout the body by relating plasma concentration to the amount of drug in the body.
• 😀 A small volume of distribution indicates that the drug is confined to the bloodstream, while a large volume suggests extensive distribution to tissues.
• 😀 The volume of distribution can sometimes exceed the total body volume, meaning the drug is concentrated in tissues outside the bloodstream.
• 😀 When calculating the volume of distribution, it's crucial to use plasma concentrations measured immediately after drug administration, before significant elimination occurs.
• 😀 If immediate post-administration samples are unavailable, the concentration is back-extrapolated from later measurements to estimate the volume of distribution.

Q & A

What is a one-compartment model in pharmacokinetics?

A one-compartment model is the simplest model where the body is conceptualized as a single tank, and the drug is administered intravenously or directly into the bloodstream over a short period of time. The drug distributes rapidly and homogeneously throughout the body.

How does a two-compartment model differ from a one-compartment model?

A two-compartment model is more complex. In this model, the drug first distributes rapidly through the central compartment (typically the blood and well-perfused organs) and then more slowly to peripheral compartments (more poorly perfused tissues). The drug moves back and forth between these compartments.

What does the plasma drug concentration time profile look like in a one-compartment model?

In a one-compartment model, the plasma drug concentration starts high and declines steadily in an exponential manner throughout the sampling period.

What is the plasma drug concentration time profile like in a two-compartment model?

In a two-compartment model, the concentration profile has two phases: a rapid decline followed by a slower decline once the drug has distributed throughout the body and plasma concentrations decrease.

What is the volume of distribution (Vd)?

The volume of distribution (Vd) is a pharmacokinetic parameter that quantifies the extent of distribution of a drug by relating the concentration measured in the plasma to the amount of drug in the body. It tells us how widely the drug has been distributed throughout the body.

How is the volume of distribution related to the distribution of the drug in the body?

If the volume of distribution is small, the drug is not widely distributed and stays mostly in the bloodstream. If the volume of distribution is large, the drug is more extensively distributed throughout tissues, resulting in lower plasma concentrations.

Can the volume of distribution exceed the total volume of the body?

Yes, the volume of distribution can be much higher than the total volume of the body. This occurs when the drug is concentrated in specific tissues outside the bloodstream, causing plasma concentrations to be very low.

How is the volume of distribution calculated?

The volume of distribution is calculated by relating the measured concentration of the drug in the plasma to the known dose administered. However, since the body starts eliminating the drug immediately after administration, it's important to use the concentration measured shortly after drug administration, before significant elimination occurs.

What challenges are associated with measuring the volume of distribution?

A challenge in measuring the volume of distribution is that it can be practically difficult or even impossible to take samples immediately after drug administration. In such cases, extrapolation from later concentration data is used to estimate the early concentration.

Why is the back extrapolation technique used to calculate the volume of distribution?

Back extrapolation is used to estimate the initial concentration of the drug immediately after administration, which is necessary for accurate calculation of the volume of distribution. This is done when it’s not feasible to obtain a sample immediately after drug administration.