Drug distribution

Drug distribution

Drug distribution is the process of delivering a drug from the bloodstream to the tissues of the body – especially the tissue(s) where its actions are needed.

Introduction to Drug Distribution

The process of transferring a drug from the bloodstream to tissues is referred to as distribution. The same principles that govern drug absorption (e.g. ionization of a drug, lipophillicity of a drug, size of a drug, pH of the environment, etc.) also govern the rate and extent that a drug will distribute to various tissues in the body.  In addition, there are additional factors at play, particularly non-specific binding to proteins.

Commonly, drugs bind non-specifically to albumin in the plasma.  Additionally, one drug, digoxin, tends to bind non-specifically to skeletal muscle, when, in fact, its desired actions occur in the heart.  When drugs bind non-specifically to proteins, their movement is limited. That is because the large proteins to which they are bound will not be able to readily distribute to other parts of the body. The protein acts as a “reservoir” of sorts.  As long as a drug is bound non-specifically to a protein, it cannot have a therapeutic action, nor can it be eliminated (metabolized hepatically by the liver or excreted by the kidneys).  Non-specific binding to drugs can also play a role in drug-drug interactions; if two or more drugs are competing for the same binding site, one drug will displace the other, thereby, leading to potential toxicity caused by the drug that was displaced.  For example, sulfonamide antibiotics are highly protein bound.  These drugs are never administered to infants less than 2 months of age because sulfonamides compete with bilirubin for binding to albumin.  When sulfonamides displace bilirubin, hyperbilirubinemia and kernicterus can result. 

Drugs will be more quickly distributed to areas of the body that receive large amounts of blood flow (e.g. heart, kidneys) than to areas that receive little blood flow (e.g. skin, adipose).  On the other hand, once a drug reaches adipose tissue, it may remain distributed here for quite a while until plasma concentrations decline and the drug can move “down its concentration gradient” back into the blood stream (e.g. “re-distribution”).

The concept of “apparent volume of distribution” is a concept that seeks to predict how extensively a drug is distributed throughout the body.  The apparent volume of distribution, Vd, is mathematically calculated by dividing the dose that is administered (mg) by the plasma concentration (mg/L).

Vd=Dose/C

Another way to think about Vd is that Vd is equal to the amount of space that a drug must fill up such that a given dose of a drug will achieve a specific plasma concentration.  There is an assumption here; that is, calculation of the apparent Vd presumes that the drug concentration is the same everywhere throughout the body. We know, in actuality, though, that this is not true since most drugs are not uniformly distributed. 

Drugs that have relatively small Vd (e.g. 5 L) largely stay in the plasma compartment.  Drugs with a Vd of 15L distribute throughout vascular and extracellular fluid compartments.  Drugs with a  Vd > 40 L distribute throughout all body tissues (vascular, extracellular, and intracellular fluid compartments).  From a practical standpoint, drugs that have a large Vd will need to be administered in larger doses to achieve a target concentration in the plasma.  In addition, drugs that are lipophillic have a larger Vd than water-soluble drugs – enabling them to accumulate in fat.  

Often the idea of some tissues being “barriers” to drug distribution is discussed (e.g. blood-brain-barrier; placental barrier).  In reality, though, if a drug is highly lipid soluble, un-ionized, and small in size, it will be able to gain access to these “restricted” tissues. 

Prof Joe Bloggs - change me!

This 2 page article describes the concepts of volume of distribution, the significance of drug binding non-specifically to proteins and tissues, and properties of drugs that readily penetrate the blood-brain barrier.

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The process of transferring a drug from the bloodstream to tissues is referred to as distribution. The same principles that govern drug absorption (e.g. ionization of a drug, lipophillicity of a drug, size of a drug, pH of the environment, etc.) also govern the rate and extent that a drug will distribute to various tissues in the body.  In addition, there are additional factors at play, particularly non-specific binding to proteins.

Commonly, drugs bind non-specifically to albumin in the plasma.  Additionally, one drug, digoxin, tends to bind non-specifically to skeletal muscle, when, in fact, its desired actions occur in the heart.  When drugs bind non-specifically to proteins, their movement is limited. That is because the large proteins to which they are bound will not be able to readily distribute to other parts of the body. The protein acts as a “reservoir” of sorts.  As long as a drug is bound non-specifically to a protein, it cannot have a therapeutic action, nor can it be eliminated (metabolized hepatically by the liver or excreted by the kidneys).  Non-specific binding to drugs can also play a role in drug-drug interactions; if two or more drugs are competing for the same binding site, one drug will displace the other, thereby, leading to potential toxicity caused by the drug that was displaced.  For example, sulfonamide antibiotics are highly protein bound.  These drugs are never administered to infants less than 2 months of age because sulfonamides compete with bilirubin for binding to albumin.  When sulfonamides displace bilirubin, hyperbilirubinemia and kernicterus can result. 

Drugs will be more quickly distributed to areas of the body that receive large amounts of blood flow (e.g. heart, kidneys) than to areas that receive little blood flow (e.g. skin, adipose).  On the other hand, once a drug reaches adipose tissue, it may remain distributed here for quite a while until plasma concentrations decline and the drug can move “down its concentration gradient” back into the blood stream (e.g. “re-distribution”).

The concept of “apparent volume of distribution” is a concept that seeks to predict how extensively a drug is distributed throughout the body.  The apparent volume of distribution, Vd, is mathematically calculated by dividing the dose that is administered (mg) by the plasma concentration (mg/L).

Vd=Dose/C

Another way to think about Vd is that Vd is equal to the amount of space that a drug must fill up such that a given dose of a drug will achieve a specific plasma concentration.  There is an assumption here; that is, calculation of the apparent Vd presumes that the drug concentration is the same everywhere throughout the body. We know, in actuality, though, that this is not true since most drugs are not uniformly distributed. 

Drugs that have relatively small Vd (e.g. 5 L) largely stay in the plasma compartment.  Drugs with a Vd of 15L distribute throughout vascular and extracellular fluid compartments.  Drugs with a  Vd > 40 L distribute throughout all body tissues (vascular, extracellular, and intracellular fluid compartments).  From a practical standpoint, drugs that have a large Vd will need to be administered in larger doses to achieve a target concentration in the plasma.  In addition, drugs that are lipophillic have a larger Vd than water-soluble drugs – enabling them to accumulate in fat.  

Often the idea of some tissues being “barriers” to drug distribution is discussed (e.g. blood-brain-barrier; placental barrier).  In reality, though, if a drug is highly lipid soluble, un-ionized, and small in size, it will be able to gain access to these “restricted” tissues. 

Prof Joe Bloggs - change me!

This set has 23 slides and describes how lipid solubility, drug ionization, drug size, pH, and non-specific protein binding influence drug distribution throughout various body “compartments”.  The concept volume of distribution is also discussed, with a variety of medication examples.

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The process of transferring a drug from the bloodstream to tissues is referred to as distribution. The same principles that govern drug absorption (e.g. ionization of a drug, lipophillicity of a drug, size of a drug, pH of the environment, etc.) also govern the rate and extent that a drug will distribute to various tissues in the body.  In addition, there are additional factors at play, particularly non-specific binding to proteins.

Commonly, drugs bind non-specifically to albumin in the plasma.  Additionally, one drug, digoxin, tends to bind non-specifically to skeletal muscle, when, in fact, its desired actions occur in the heart.  When drugs bind non-specifically to proteins, their movement is limited. That is because the large proteins to which they are bound will not be able to readily distribute to other parts of the body. The protein acts as a “reservoir” of sorts.  As long as a drug is bound non-specifically to a protein, it cannot have a therapeutic action, nor can it be eliminated (metabolized hepatically by the liver or excreted by the kidneys).  Non-specific binding to drugs can also play a role in drug-drug interactions; if two or more drugs are competing for the same binding site, one drug will displace the other, thereby, leading to potential toxicity caused by the drug that was displaced.  For example, sulfonamide antibiotics are highly protein bound.  These drugs are never administered to infants less than 2 months of age because sulfonamides compete with bilirubin for binding to albumin.  When sulfonamides displace bilirubin, hyperbilirubinemia and kernicterus can result. 

Drugs will be more quickly distributed to areas of the body that receive large amounts of blood flow (e.g. heart, kidneys) than to areas that receive little blood flow (e.g. skin, adipose).  On the other hand, once a drug reaches adipose tissue, it may remain distributed here for quite a while until plasma concentrations decline and the drug can move “down its concentration gradient” back into the blood stream (e.g. “re-distribution”).

The concept of “apparent volume of distribution” is a concept that seeks to predict how extensively a drug is distributed throughout the body.  The apparent volume of distribution, Vd, is mathematically calculated by dividing the dose that is administered (mg) by the plasma concentration (mg/L).

Vd=Dose/C

Another way to think about Vd is that Vd is equal to the amount of space that a drug must fill up such that a given dose of a drug will achieve a specific plasma concentration.  There is an assumption here; that is, calculation of the apparent Vd presumes that the drug concentration is the same everywhere throughout the body. We know, in actuality, though, that this is not true since most drugs are not uniformly distributed. 

Drugs that have relatively small Vd (e.g. 5 L) largely stay in the plasma compartment.  Drugs with a Vd of 15L distribute throughout vascular and extracellular fluid compartments.  Drugs with a  Vd > 40 L distribute throughout all body tissues (vascular, extracellular, and intracellular fluid compartments).  From a practical standpoint, drugs that have a large Vd will need to be administered in larger doses to achieve a target concentration in the plasma.  In addition, drugs that are lipophillic have a larger Vd than water-soluble drugs – enabling them to accumulate in fat.  

Often the idea of some tissues being “barriers” to drug distribution is discussed (e.g. blood-brain-barrier; placental barrier).  In reality, though, if a drug is highly lipid soluble, un-ionized, and small in size, it will be able to gain access to these “restricted” tissues. 

Prof Joe Bloggs - change me!

There are four interactive modules that allow users to get a better understanding of VD. The first is a simple container in which learners can “inject” drug into different containers and view what happens to drug concentration and see how this relates to volume.  In the second module, users can inject drug and see what happens as drug distributes more widely throughout various compartments.  The third module relates VD concepts to the human body; for drugs with a large VD, users can observe how drugs distribute outside the bloodstream whereas drugs with a small VD stay mainly in the vasculature.  The final module illustrates relationships between VD and loading dose.  Users can change the parameters in each module using sliders.

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